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  • 1.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Exploring the pancreas with optical projection tomography2012Inngår i: Imaging in Medicine, ISSN 1755-5191, Vol. 4, nr 1, 5-7 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 2.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Imaging shows insulin-producing cells in diabetes2013Inngår i: TrAC. Trends in analytical chemistry, ISSN 0165-9936, Vol. 44, III-III s.Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 3.
    Ahlgren, Ulf
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gotthardt, Martin
    Department of Nuclear Medicine, Nijmegen, Netherlands.
    Approaches for imaging islets2010Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 654, 39-57 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The establishment of improved technologies for imaging of the pancreas is a key element in addressing several aspects of diabetes pathogenesis. In this respect, the development of a protocol that allows for non-invasive scoring of human islets, or islet beta-cells, is of particular importance. The development of such a technology would have profound impact on both clinical and experimental medicine, ranging from early diagnosis of diabetes to the evaluation of therapeutic regimes. Another important task is the development of modalities for high-resolution imaging of experimental animal models for diabetes. Rodent models for diabetes research have for decades been instrumental to the diabetes research community. The ability to image, and to accurately quantify, key players of diabetogenic processes with molecular specificity will be of great importance for elucidating mechanistic aspects of the disease. This chapter aims to overview current progress within these research areas.

  • 4.
    Ahlgren, Ulf
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Optical imaging of islets: new possibilities by the development of infrared fluorescent proteins2009Inngår i: Islets, ISSN 1938-2022, Vol. 1, nr 2, 163-164 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The capacity to record the spatial and quantitative distribution of cellular subtypes involved in diabetogenic processes is a key element in experimental diabetes research. A non-invasive technique to accurately monitor parameters such as pancreatic β-cell mass (BCM) and its distribution would provide a stepping stone in understanding different aspects of diabetes pathogenesis. It would also assist in the development of therapeutic regimes by providing a tool for the evaluation of anti-diabetic drugs or other curative or diagnostic measures. At present, a range of imaging modalities are being explored for this purpose. Whereas nuclear imaging techniques, characterised by their high tissue penetration depth but relatively low spatial resolution, appear most promising for the study of humans and large animals, optical imaging enables a route to cost-effective, high sensitivity, high resolution imaging in rodent models for disease. In this commentary, the potential impact of infrared fluorescent proteins (IFPs), as recently reported by Shu et al in Science, for imaging of the pancreas in small animals will be discussed.

  • 5.
    Ahlgren, Ulf
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kostromina, Elena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Imaging the pancreatic beta cell: chapter 132011Inngår i: Type 1 diabetes: pathogenesis, genetics and immunotherapy / [ed] David Wagner, InTech, 2011Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    This book is a compilation of reviews about the pathogenesis of Type 1 Diabetes. T1D is a classic autoimmune disease. Genetic factors are clearly determinant but cannot explain the rapid, even overwhelming expanse of this disease. Understanding etiology and pathogenesis of this disease is essential. A number of experts in the field have covered a range of topics for consideration that are applicable to researcher and clinician alike. This book provides apt descriptions of cutting edge technologies and applications in the ever going search for treatments and cure for diabetes. Areas including T cell development, innate immune responses, imaging of pancreata, potential viral initiators, etc. are considered.

  • 6.
    Alanentalo, Tomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Optical projection tomography based 3D-spatial and quantitative assessments of the diabetic pancreas2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The gastrointestinal tract comprises a number of digestive organs including the stomach and pancreas. The stomach is involved in the digestion and short term storage of food while the pancreas is a mixed endocrine and exocrine gland which provides the body with hormones and enzymes essential for nutritional utilisation. The pancreas consists of three different cell lineages, acinar, ductal and endocrine cells. The endocrine cells, organised in the islets of Langerhans, are scattered throughout the exocrine parenchyma and regulate blood glucose levels by production of hormones such as glucagon and insulin.

    The Nkx family of homeodomain proteins controls numerous processes during development. Previous studies have identified two members belonging to the Nkx6 subfamily of Nkx proteins, Nkx6.1 and Nkx6.2. We have described the cloning and embryonic expression pattern of Nkx6.3. All three members of the Nkx6 gene family were shown to be expressed in partially overlapping domains during the development of the gastrointestinal tract and the central nervous system. Nkx6.2 was also identified as a transient marker for pancreatic exocrine cells.

    Analysing gene expression patterns and morphological features in tissues and organs is often performed by stereologic sampling which is a labour-intensive two dimensional approach that rely on certain assumptions when calculating e.g. β-cell mass and islet number in the pancreas. By combined improvements in immunohistochemical protocols, computational processing and tomographic scanning, we have developed a methodology based on optical projection tomography (OPT) allowing for 3D visualisation and quantification of specifically labelled objects within intact adult mouse organs. In the pancreas, this technique allows for spatial and quantitative measurements of total islet number and β-cell mass. We have further developed a protocol allowing for high resolution regional analyses based on global OPT assessments of the pancreatic constitution. This methodology is likely to facilitate detailed cellular and molecular analysis of user defined regions of interest in the pancreas, at the same time providing information on the overall disease state of the gland.

    Type 1 diabetes mellitus (T1D) can occur at any age and is characterized by the marked inability of the pancreas to secrete insulin due to an autoimmune destruction of the insulin producing β-cells. Information on the key cellular and molecular events underlying the recruitment of lymphocytes, their infiltration of the islets of Langerhans and consequent β-cell destruction is essential for understanding the pathogenesis of T1D. Using the developed methodology we have recorded the spatial and quantitative distribution of islet β-cells and infiltrating lymphocytes in the non obese diabetic (NOD) mouse model for T1D. This study shows that the smaller islets, which are predominantly organised in the periphery of the organ, are the first to disappear during the progression of T1D. The larger islets appear more resistant and our data suggest that a compensatory proliferative process is going on side by side with the autoimmune-induced β-cell destruction. Further, the formation of structures resembling tertiary lymphoid organs (TLOs) in areas apparently unaffected by insulitis suggests that local factors may provide cues for the homing of these lymphocytes back to the pancreas.

  • 7.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Asayesh, Amir
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Morrison, Harris
    Lorén, Christina E
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sharpe, James
    Ahlgren, Ulf
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Tomographic molecular imaging and 3D quantification within adult mouse organs.2007Inngår i: Nature Methods, ISSN 1548-7091, Vol. 4, nr 1, 31-33 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Chatonnet, Fabrice
    Karlen, Mattias
    Sulniute, Rima
    Ericson, Johan
    Andersson, Elisabet
    Ahlgren, Ulf
    Cloning and analysis of Nkx6.3 during CNS and gastrointestinal development2006Inngår i: Gene expression patterns, ISSN 1567-133X, Vol. 6, nr 2, 162-170 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 9.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nilsson, Anna Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sharpe, James
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, 1756-1764 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 10.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lorén, Christina E
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Larefalk, Asa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sharpe, James
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas2008Inngår i: Journal of Biomedical Optics, ISSN 1083-3668, Vol. 13, nr 5, 054070- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A predicament when assessing the mechanisms underlying the pathogenesis of type-1 diabetes (T1D) has been to maintain simultaneous global and regional information on the loss of insulin-cell mass and the progression of insulitis. We present a procedure for high-resolution 3-D analyses of regions of interest (ROIs), defined on the basis of global assessments of the 3-D distribution, size, and shape of molecularly labeled structures within the full volume of the intact mouse pancreas. We apply a refined protocol for optical projection tomography (OPT)-aided whole pancreas imaging in combination with confocal laser scanning microscopy of site-directed pancreatic microbiopsies. As such, the methodology provides a useful tool for detailed cellular and molecular assessments of the autoimmune insulitis in T1D. It is anticipated that the same approach could be applied to other areas of research where 3-D molecular distributions of both global and regional character is required.

  • 11. Ali, Yusuf
    et al.
    Diez, Juan
    Selander, Lars
    Zheng, Xiaofeng
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
    Berggren, Per-Olof
    The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice2016Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, nr 5, 1007-1011 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo imaging of the developing pancreas is challenging due to the inaccessibility of the tissue. To circumvent this, on embryonic day 10.5 (E10.5) we transplanted a mouse developing pancreatic bud into the anterior chamber of the eye (ACE) to determine whether the eye is a useful transplant site to support pancreas development. We transplanted an E10.5 dorsal pancreatic bud into the ACE of a syngeneic recipient mouse. Using a mouse insulin promoter-green fluorescent protein (MIP-GFP) mouse as the tissue donor, we non-invasively imaged the pancreatic bud as it develops at single beta cell resolution across time. The transplanted pancreatic bud rapidly engrafts and vascularises when transplanted into the ACE. The pancreatic progenitor cells differentiate into exocrine and endocrine cells, including cells expressing insulin, glucagon and somatostatin. The morphology of the transplanted pancreatic bud resembles that of the native developing pancreas. Beta cells within the transplanted pancreatic bud respond to glucose in a manner similar to that of native fetal beta cells and superior to that of in vitro developed beta cells. Unlike in vitro grown pancreatic explants, pancreatic tissue developing in the ACE is vascularised, providing the developing pancreatic tissue with a milieu resembling the native situation. Altogether, we show that the ACE is able to support growth, differentiation and function of a developing pancreatic bud across time in vivo.

  • 12.
    Andreae, Laura C
    et al.
    MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Campus, London, UK.
    Lumsden, Andrew
    MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Campus, London, UK.
    Gilthorpe, Jonathan D
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Chick Lrrn2, a novel downstream effector of Hoxb1 and Shh, functions in the selective targeting of rhombomere 4 motor neurons2009Inngår i: Neural development, ISSN 1749-8104, Vol. 4, 27- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background; Capricious is a Drosophila adhesion molecule that regulates specific targeting of a subset of motor neurons to their muscle target. We set out to identify whether one of its vertebrate homologues, Lrrn2, might play an analogous role in the chick.

    Results; We have shown that Lrrn2 is expressed from early development in the prospective rhombomere 4 (r4) of the chick hindbrain. Subsequently, its expression in the hindbrain becomes restricted to a specific group of motor neurons, the branchiomotor neurons of r4, and their pre-muscle target, the second branchial arch (BA2), along with other sites outside the hindbrain. Misexpression of the signalling molecule Sonic hedgehog (Shh) via in ovo electroporation results in upregulation of Lrrn2 exclusively in r4, while the combined expression of Hoxb1 and Shh is sufficient to induce ectopic Lrrn2 in r1/2. Misexpression of Lrrn2 in r2/3 results in axonal rerouting from the r2 exit point to the r4 exit point and BA2, suggesting a direct role in motor axon guidance.

    Conclusion; Lrrn2 acts downstream of Hoxb1 and plays a role in the selective targeting of r4 motor neurons to BA2.

  • 13. Annicotte, Jean-Sébastien
    et al.
    Fayard, Elisabeth
    Swift, Galvin H
    Selander, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Tanaka, Toshiya
    Kodama, Tatsuhiko
    Schoonjans, Kristina
    Auwerx, Johan
    Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development.2003Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 23, nr 19, 6713-6124 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Liver receptor homolog 1 (LRH-1) and pancreatic-duodenal homeobox 1 (PDX-1) are coexpressed in the pancreas during mouse embryonic development. Analysis of the regulatory region of the human LRH-1 gene demonstrated the presence of three functional binding sites for PDX-1. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed that PDX-1 bound to the LRH-1 promoter, both in cultured cells in vitro and during pancreatic development in vivo. Retroviral expression of PDX-1 in pancreatic cells induced the transcription of LRH-1, whereas reduced PDX-1 levels by RNA interference attenuated its expression. Consistent with direct regulation of LRH-1 expression by PDX-1, PDX-1(-/-) mice expressed smaller amounts of LRH-1 mRNA in the embryonic pancreas. Taken together, our data indicate that PDX-1 controls LRH-1 expression and identify LRH-1 as a novel downstream target in the PDX-1 regulatory cascade governing pancreatic development, differentiation, and function.

  • 14. Aquino, Jorge B
    et al.
    Hjerling-Leffler, Jens
    Koltzenburg, Martin
    Edlund, Thomas
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Villar, Marcelo J
    Ernfors, Patrik
    In vitro and in vivo differentiation of boundary cap neural crest stem cells into mature Schwann cells.2006Inngår i: Experimental Neurology, ISSN 0014-4886, Vol. 198, nr 2, 438-49 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 15.
    Asayesh, Amir
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Spleno-pancreatic development assessed by 3D molecular imaging2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The development of different organs and tissues along the gastrointestinal tract, including the pancreas, depends on signalling between the endoderm and the adjacent mesenchyme. The Nkx gene Bapx1 is involved in spatial control of organ-positioning in the spleno-pancreatic region, and deficiency in this gene results in unacceptable proximity of the splenic mesenchyme to the pancreas. This permits agitating signals from the splenic mesenchyme to induce an in vivo (and in vitro) transformation of pancreatic epithelium to a cystic structure with gut like features. Also, wild type splenic mesenchyme is competent to induce a similar transformation. These findings illustrate the importance for strict control of organ positioning during spleno-pancreatic development.

    Several growth factors and receptors involved in pancreatic development are activated by protease processing. Some of these growth factors have been implicated as substrates for members of the A Disintegrin And Metalloprotease (ADAM) family. The ADAMs 9, 10, and 17 are expressed during pancreatic development and in the adult pancreas, suggesting a possible role for these ADAMs in pancreatic development and function.

    Animal model systems are widely used to investigate gene function during development and disease. However, spatial, molecular, and quantitative phenotype screening in animals is a time consuming effort. Optical Projection Tomography is a 3-dimensional imaging technique that, in combination with improvements in sample preparation and computer processing, can be used to visualize and quantify characteristics of intact adult mouse organs such as the total β-cell content in the pancreas.

  • 16.
    Asayesh, Amir
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Alanentalo, Tomas
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Khoo, Nelson K S
    Ahlgren, Ulf
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments.2005Inngår i: Developmental Dynamics, ISSN 1058-8388, Vol. 232, nr 4, 1105-1114 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 17.
    Asayesh, Amir
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Sharpe, James
    Watson, Robert P
    Hecksher-Sørensen, Jacob
    Hastie, Nicholas D
    Hill, Robert E
    Ahlgren, Ulf
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1-/- mice.2006Inngår i: Genes & Development, ISSN 0890-9369, Vol. 20, nr 16, 2208-2213 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 18. Baeyens, Luc
    et al.
    Lemper, Marie
    Leuckx, Gunter
    De Groef, Sofie
    Bonfanti, Paola
    Stange, Geert
    Shemer, Ruth
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Scheel, David W
    Pan, Fong C
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gu, Guoqiang
    Stoffers, Doris A
    Dor, Yuval
    Ferrer, Jorge
    Gradwohl, Gerard
    Wright, Christopher VE
    Van de Casteele, Mark
    German, Michael S
    Bouwens, Luc
    Heimberg, Harry
    Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice2014Inngår i: Nature Biotechnology, ISSN 1087-0156, Vol. 32, nr 1, 76-83 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.

  • 19.
    Berghard, Anna
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Bohm, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons2012Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, nr 8, 3464-3472 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.

  • 20.
    Bergman, Marie-Louise
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Cilio, Corrado M
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, 2780, Oeiras, Portugal.
    Lamhamedi-Cherradi, Salah-Eddine
    INSERM U25, Hopital Necker, 75743, Paris, France.
    Löfgren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Colucci, Francesco
    Laboratory for cytokines and lymphoid development, Pasteur Institute, 75015 Paris, France.
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Garchon, Henri-Jean
    INSERM U25, Hopital Necker, 75743, Paris, France.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice2001Inngår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, nr 2, 105-113 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

  • 21.
    Bergman, Marie-Louise
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Duarte, Nadia
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Motta, Vinicius
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Penha-Goncalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, nr 7, 1677-1682 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

  • 22.
    Bergqvist, Ingela
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Saarikettu, Juha
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Eriksson, Björn
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Corneliussen, Brit
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Grundström, Thomas
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak). Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development2000Inngår i: European Journal of Immunology, ISSN 0014-2980, Vol. 30, nr 10, 2857-2863 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    E2A, HEB and E2-2 genes encode a group of basic helix-loop-helix (bHLH) transcription factors that are structurally and functionally similar. Deletion of the genes encoding either of these proteins leads to early lethality and a block in B lymphocyte development. Evidence for a function in T lymphocyte development has, however, only been reported for E2A and HEB. To further elucidate the role of E2-2 at developmental stages that have proven difficult to study due to the early lethality phenotype of mice defective in E2-2, we generated and analyzed mice conditionally mutated in the E2-2 gene. These mice are mosaic with respect to E2-2 expression, consisting of cells with either one functional and one null mutated E2-2 allele or two null mutated alleles. Using this experimental model, we find that cells with a homozygous null mutated E2-2 gene are under-represented in B lymphocyte as well as T lymphocyte cell lineages as compared to other hematopoietic or non-hematopoietic cell lineages. Our data suggests that E2-2 deficiency leads to a partial block in both B and T lymphocyte development. The block in T cell development appears to occur at an early stage in differentiation, since skewing in the mosaicism is observed already in CD4+8+ double-positive thymocytes.

  • 23.
    Boucher, Marie-Josée
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Selander, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Lennart
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms.2006Inngår i: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, nr 10, 6395-403 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 24. Boucher, Marie-Josée
    et al.
    Simoneau, Mélanie
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The homeodomain-interacting protein kinase 2 regulates insulin promoter factor-1/pancreatic duodenal homeobox-1 transcriptional activity2009Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, nr 1, 87-97 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of the Ipf1/Pdx1 gene in beta-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12-15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or beta-cell function, is regulated.

  • 25.
    Burguière, Anne-Cecile
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Hanna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    von Hofsten, Jonas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Alkali-like myosin light chain-1 (myl1) is an early marker for differentiating fast muscle cells in zebrafish2011Inngår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 240, nr 7, 1856-1863 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During myogenesis, muscle precursors become divided into either fast- or slow-twitch fibres, which in the zebrafish occupy distinct domains in the embryo. Genes encoding sarcomeric proteins specific for fast or slow fibres are frequently used as lineage markers. In an attempt to identify and evaluate early definitive markers for cells in the fast-twitch pathway, we analysed genes encoding proteins contributing to the fast sarcomeric structures. The previously uncharacterized zebrafish alkali-like myosin light chain gene (myl1) was found to be expressed exclusively in cells in the fast-twitch pathway initiated at an early stage of fast fibre differentiation. Myl1 was expressed earlier, and in a more fibre type restricted manner, than any of the previously described and frequently used fast myosin light and heavy chain and troponin muscle markers mylz2, mylz3, tnni2, tnnt3a, fMyHC1.3. In summary, this study introduces a novel marker for early differentiating fast muscle cells.

  • 26.
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Periodiskt uttryck av genen Lhx2 reglerar hårväxten2010Inngår i: Läkartidningen, ISSN 0023-7205, Vol. 107, nr 24-25, 1616- s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 27.
    Cheddad, Abbas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Prunskaite-Hyyryläinen, Renata
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Georgsson, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Vainio, Seppo
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion2013Inngår i: Optics Express, ISSN 1094-4087, Vol. 21, nr 14, 16584-16604 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods.

  • 28.
    Cheddad, Abbas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Svensson, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Sharpe, James
    Georgsson, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Image processing assisted algorithms for optical projection tomography2012Inngår i: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 31, nr 1, 1-15 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since it was first presented in 2002, optical projection tomography (OPT) has emerged as a powerful tool for the study of biomedical specimen on the mm to cm scale. In this paper, we present computational tools to further improve OPT image acquisition and tomographic reconstruction. More specifically, these methods provide: semi-automatic and precise positioning of a sample at the axis of rotation and a fast and robust algorithm for determination of postalignment values throughout the specimen as compared to existing methods. These tools are easily integrated for use with current commercial OPT scanners and should also be possible to implement in "home made" or experimental setups for OPT imaging. They generally contribute to increase acquisition speed and quality of OPT data and thereby significantly simplify and improve a number of three-dimensional and quantitative OPT based assessments.

  • 29.
    Chen, Changchun
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Tuck, Simon
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Byström, Anders S
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants2009Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 5, nr 7, e1000561- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5'methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development.

  • 30. Chotard, Laëtitia
    et al.
    Mishra, Ashwini K
    Sylvain, Marc-André
    Tuck, Simon
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lambright, David G
    Rocheleau, Christian E
    TBC-2 regulates RAB-5/RAB-7-mediated endosomal trafficking in Caenorhabditis elegans2010Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 21, nr 13, 2285-2296 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During endosome maturation the early endosomal Rab5 GTPase is replaced with the late endosomal Rab7 GTPase. It has been proposed that active Rab5 can recruit and activate Rab7, which in turn could inactivate and remove Rab5. However, many of the Rab5 and Rab7 regulators that mediate endosome maturation are not known. Here, we identify Caenorhabditis elegans TBC-2, a conserved putative Rab GTPase-activating protein (GAP), as a regulator of endosome to lysosome trafficking in several tissues. We show that tbc-2 mutant animals accumulate enormous RAB-7-positive late endosomes in the intestine containing refractile material. RAB-5, RAB-7, and components of the homotypic fusion and vacuole protein sorting (HOPS) complex, a RAB-7 effector/putative guanine nucleotide exchange factor (GEF), are required for the tbc-2(-) intestinal phenotype. Expression of activated RAB-5 Q78L in the intestine phenocopies the tbc-2(-) large late endosome phenotype in a RAB-7 and HOPS complex-dependent manner. TBC-2 requires the catalytic arginine-finger for function in vivo and displays the strongest GAP activity on RAB-5 in vitro. However, TBC-2 colocalizes primarily with RAB-7 on late endosomes and requires RAB-7 for membrane localization. Our data suggest that TBC-2 functions on late endosomes to inactivate RAB-5 during endosome maturation.

  • 31. Correa-Medina, Mayrin
    et al.
    Bravo-Egana, Valia
    Rosero, Samuel
    Ricordi, Camillo
    Diez, Juan
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Pastori, Ricardo L
    MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas.2009Inngår i: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 9, nr 4, 193-9 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MicroRNAs (miRNA) are small non-coding RNAs that inhibit gene expression through binding to complementary messenger RNA sequences. miRNAs have been predicted to target genes important for pancreas development, proper endocrine cell function and metabolism. We previously described that miRNA-7 (miR-7) was the most abundant and differentially expressed islet miRNA, with 200-fold higher expression in mature human islets than in acinar tissue. Here we have analyzed the temporal and spatial expression of miR-7 in human fetal pancreas from 8 to 22 weeks of gestational age (wga). Human fetal (8-22wga) and adult pancreases were processed for immunohistochemistry, in situ hybridization, and quantitative RT-PCR of miRNA and mRNA. miR-7 was expressed in the human developing pancreas from around 9wga and reached its maximum expression levels between 14 and 18wga, coinciding with the exponential increase of the pancreatic endocrine hormones. Throughout development miR-7 expression was preferentially localized to endocrine cells and its expression persisted in the adult pancreas. The present study provides a detailed analysis of the spatiotemporal expression of miR-7 in developing human pancreas. The specific localization of miR-7 expression to fetal and adult endocrine cells indicates a potential role for miR-7 in endocrine cell differentiation and/or function. Future functional studies of a potential role for miR-7 function in islet cell differentiation and physiology are likely to identify novel targets for the treatment of diabetes and will lead to the development of improved protocols for generating insulin-producing cells for cell replacement therapy.

  • 32. Crabtree, Judy S
    et al.
    Scacheri, Peter C
    Ward, Jerrold M
    McNally, Sara R
    Swain, Gary P
    Montagna, Cristina
    Hager, Jeffrey H
    Hanahan, Douglas
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Magnuson, Mark A
    Garrett-Beal, Lisa
    Burns, A Lee
    Ried, Thomas
    Chandrasekharappa, Settara C
    Marx, Stephen J
    Spiegel, Allen M
    Collins, Francis S
    Of mice and MEN1: Insulinomas in a conditional mouse knockout.2003Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 23, nr 17, 6075-6085 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis.

  • 33.
    Dahl, Lina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Stem cell function and organ development: analysis of Lhx2 function in hematopoietic stem cells and eye development2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    When a multicellular organism suffers damages to tissues/organs it heals itself by either substituting the lost cellular matrix by scar formation or by regenerating the lost tissue. Regeneration likely occurs by a recapitulation of the developmental process that formed the organ. Many processes regulating organ development are based on epithelial-mesenchymal interactions and a strict control of organ specific stem/progenitor cells. Elucidation of the molecular basis of these processes is therefore vital in order to develop novel therapies in regenerative medicine. The LIM homebox gene Lhx2 is interesting in this context since Lhx2 has been shown to be important for the formation of several organs by regulating epithelial-mesenchymal interactions and progenitor cell function. Targeted inactivation of Lhx2 leads to a lethal anemia due to malformed liver and severe neural abnormalities such as hypoplasia of the forebrain and anophtalmia. Thus, elucidation of the mechanisms of the function of Lhx2 in different organ systems would give important insights into the molecular mechanisms regulating epithelial-mesenchymal interactions and stem/progenitor cell function.

    To elucidate the function of Lhx2 in the hematopoietic system Lhx2 was initially expressed in hematopoietic progenitor cells derived from ES cells differentiated in vitro using retroviral vectors. This approach led to the generation of hematopoietic stem cell (HSC)-like cell lines suggesting that Lhx2 could impact HSC function. However neither the specificity nor the efficiency of the Lhx2-induced phenotype could be determined using this approach. To be able to elucidate the function of Lhx2 in the hematopoietic system, an ES cell line with inducible Lhx2 expression was generated. Lhx2 expression induces self-renewal of a distinct hematopoietic progenitor cell from which HSC-like cell lines were established. Down-regulation of Lhx2 in these HSC-like cell lines leads to a rapid loss of stem cell character, providing a good model to study the molecular function of Lhx2 in hematopoietic stem/progenitor cells. A global gene expression analysis was performed comparing the Lhx2+ stem cell population to the Lhx2- differentiated progeny. This approach identified genes putatively linked to self-renewal/differentiation of HSCs. A considerable proportion of the genes showed an overlapping gene expression pattern with Lhx2 expression in tissue of non-hematopoietic origin suggesting that Lhx2 function in stem/progenitor cells partly overlap with Lhx2 function during organ development.

    In order to define other Lhx2-dependent progenitor cell populations and to generate a tool to analyze the function of Lhx2 in organ development a new transgenic mouse model was generated. By using a specific part of the Lhx2 promoter to drive expression of Cre recombinase in vivo (Lhx2-Cre mice) we have been able to define the first eye committed progenitor cells in the forebrain. By using the Lhx2-Cre mice it will be possible to distinguish the function of genes during eye development from their function in the patterning of the forebrain e.g. the eye field transcription factors. Conditional inactivation of Lhx2 in these eye specific progenitor cells causes an immediate developmental arrest. The transgene is also active in Lhx2-/- embryonic forebrain, but re-expression of Lhx2 in Lhx2-/- progenitor cells only promote formation of retinal pigment epithelium cells. Analysis of genes expressed by the Lhx2+ stem cell population allowed us to define novel genes putatively linked to Lhx2 function in eye development. Thus, we have defined the progenitor cells in the forebrain committed to eye development and the expansion and patterning of these progenitors are dependent on Lhx2. Although commitment to eye development is Lhx2-independent, Lhx2 might be important for the acquisition of the oligopotent fate of these progenitor cells.

  • 34.
    Dahl, Lina
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Richter, Karin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lhx2 promotes self-renewal of a distinct multipotent hematopoietic progenitor cell in embryoid bodies2008Inngår i: PLoS one, ISSN 1932-6203, Vol. 3, nr 4, e2025- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The molecular mechanisms regulating the expansion of the hematopoietic system including hematopoietic stem cells (HSCs) in the fetal liver during embryonic development are largely unknown. The LIM-homeobox gene Lhx2 is a candidate regulator of fetal hematopoiesis since it is expressed in the fetal liver and Lhx2−/− mice die in utero due to severe anemia. Moreover, expression of Lhx2 in embryonic stem (ES) cell-derived embryoid bodies (EBs) can lead to the generation of HSC-like cell lines. To further define the role of this transcription factor in hematopoietic regulation, we generated ES cell lines that enabled tet-inducible expression of Lhx2. Using this approach we observed that Lhx2 expression synergises with specific signalling pathways, resulting in increased frequency of colony forming cells in developing EB cells. The increase in growth factor-responsive progenitor cells directly correlates to the efficiency in generating HSC-like cell lines, suggesting that Lhx2 expression induce self-renewal of a distinct multipotential hematopoietic progenitor cell in EBs. Signalling via the c-kit tyrosine kinase receptor and the gp130 signal transducer by IL-6 is necessary and sufficient for the Lhx2 induced self-renewal. While inducing self-renewal of multipotential progenitor cells, expression of Lhx2 inhibited proliferation of primitive erythroid precursor cells and interfered with early ES cell commitment, indicating striking lineage specificity of this effect.

  • 35.
    Dennhag, Nils
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Masterprogrammet i biomedicin.
    Analysis of Paired box protein Pax3 and Pax7 mutant Zebrafish Danio rerio2015Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
  • 36.
    Domellöf, Fatima Pedrosa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Parkkonen, Kimmo
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Lindström, Mona
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Nord, Hanna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    von Hoffsten, Jonas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Li, Zhenlin
    Univ Paris 06, CNRS, INSERM, Inst Biol Paris Seine, Paris, France.
    Desmin in extraocular muscles2015Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, nr 7Artikkel i tidsskrift (Annet vitenskapelig)
  • 37. Domínguez-Bendala, Juan
    et al.
    Klein, Dagmar
    Ribeiro, Melina
    Ricordi, Camillo
    Inverardi, Luca
    Pastori, Ricardo
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro.2005Inngår i: Diabetes, ISSN 0012-1797, Vol. 54, nr 3, 720-6 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 38.
    Edfalk, Sara
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Steneberg, Pär
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.2008Inngår i: Diabetes, ISSN 1939-327X, Vol. 57, nr 9, 2280-7 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: The G-protein-coupled receptor Gpr40 is expressed in beta-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion. However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5'-flanking region of Gpr40, implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS: In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1-null and beta-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS: Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in beta-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS: Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from beta-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.

  • 39.
    Edling, Charlotte E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pedersen, Malin
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Rönnstrand, Lars
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Palmer, Ruth H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå centrum för molekylär patogenes (UCMP).
    Hallberg, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haematopoietic progenitor cells utilise conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation2007Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 136, nr 2, 260-268 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall tyrosine phosphorylation of c-Kit upon SF stimulation. This report showed that this specific feedback mechanism of c-PKC mediated phosphorylation of the c-Kit receptor has consequences for both proliferation and survival of HSC-like cell lines.

  • 40.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Söderström, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Löfgren-Burström, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Asplund, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, nr 1, 81-84 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 41. Elle, Ida C
    et al.
    Simonsen, Karina T
    Olsen, Louise C B
    Birck, Pernille K
    Ehmsen, Sidse
    Tuck, Simon
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Le, Thuc T
    Færgeman, Nils J
    Tissue- and paralogue-specific functions of acyl-CoA-binding proteins in lipid metabolism in Caenorhabditis elegans2011Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 437, nr 2, 231-241 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ACBP (acyl-CoA-binding protein) is a small primarily cytosolic protein that binds acyl-CoA esters with high specificity and affinity. ACBP has been identified in all eukaryotic species, indicating that it performs a basal cellular function. However, differential tissue expression and the existence of several ACBP paralogues in many eukaryotic species indicate that these proteins serve distinct functions. The nematode Caenorhabditis elegans expresses seven ACBPs: four basal forms and three ACBP domain proteins. We find that each of these paralogues is capable of complementing the growth of ACBP-deficient yeast cells, and that they exhibit distinct temporal and tissue expression patterns in C. elegans. We have obtained loss-of-function mutants for six of these forms. All single mutants display relatively subtle phenotypes; however, we find that functional loss of ACBP-1 leads to reduced triacylglycerol (triglyceride) levels and aberrant lipid droplet morphology and number in the intestine. We also show that worms lacking ACBP-2 show a severe decrease in the β-oxidation of unsaturated fatty acids. A quadruple mutant, lacking all basal ACBPs, is slightly developmentally delayed, displays abnormal intestinal lipid storage, and increased β-oxidation. Collectively, the present results suggest that each of the ACBP paralogues serves a distinct function in C. elegans.

  • 42.
    Eriksson, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Svensson, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Cheddad, Abbas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kostromina, Elena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Norlin, Nils
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Pilleggi, Antonello
    Cell Transplants Center, Diabetes Research Institute, University of Miami.
    Sharpe, James
    EMBL-CRG Systems Biology Program, Centre for Genomic Regulation, Catalan Institute of Research and Advance Studies.
    Georgsson, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Alanentalo, Tomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Near infrared optical projection tomography for assessments of β-cell mass distribution in diabetes research2013Inngår i: Journal of Visualized Experiments, ISSN 1940-087X, Vol. 71, nr e50238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)2; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction2 and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations3. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.

  • 43. Eter, Wael A.
    et al.
    Parween, Saba
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Joosten, Lieke
    Frielink, Cathelijne
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Brom, Maarten
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gotthardt, Martin
    SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 24576Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

  • 44. Fujitani, Yoshio
    et al.
    Fujitani, Shuko
    Luo, Huijun
    Qiu, Feng
    Burlison, Jared
    Long, Qiaoming
    Kawaguchi, Yoshiya
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    MacDonald, Raymond J
    Furukawa, Takahisa
    Fujikado, Takashi
    Magnuson, Mark A
    Xiang, Mengqing
    Wright, Christopher V E
    Ptf1a determines horizontal and amacrine cell fates during mouse retinal development.2006Inngår i: Development, ISSN 0950-1991, Vol. 133, nr 22, 4439-50 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 45. Gao, Tao
    et al.
    McKenna, Brian
    Li, Changhong
    Reichert, Maximilian
    Nguyen, James
    Singh, Tarjinder
    Yang, Chenghua
    Pannikar, Archana
    Doliba, Nicolai
    Zhang, Tingting
    Stoffers, Doris A.
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Matschinsky, Franz
    Stein, Roland
    Stanger, Ben Z.
    Pdx1 Maintains beta Cell Identity and Function by Repressing an alpha Cell Program2014Inngår i: Cell Metabolism, ISSN 1550-4131, Vol. 19, nr 2, 259-271 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult beta cell function. In this study, we traced the fate of adult beta cells after Pdx1 deletion. As expected, beta-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of a cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the alpha cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of alpha cells. These findings indicate that Pdx1 acts as a master regulator of beta cell fate by simultaneously activating genes essential for beta cell identity and repressing those associated with alpha cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of beta cell identity contributes to the pathogenesis of type 2 diabetes.

  • 46.
    Goulley, Joan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Role of BMP signaling and ASNA1 in β-cells2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Patients with type II diabetes present alterations in glucose homeostasis due to insufficient amount of insulin (β-cell dysfunction) and inability to properly use the insulin that is secreted (insulin resistance). Combined genetical and environmental factors are believed to be responsible for these dysfunctions and the resulting impairment in glucose homeostasis. The pancreatic gland is composed of exocrine and endocrine tissues. The endocrine part of the organ couples glucose sensing to insulin release. Within this endocrine gland, also known as islets of Langerhans, the insulin secreting β-cell is the main player and therefore highly important for proper glucose metabolism. In this thesis, mice were developed in order to assess the role of BMP signaling molecule and Arsenite induced ATPase-1 (Asna1) for pancreas development and β-cell function.

    The mature β-cell responds to elevated glucose levels by secreting insulin in a tightly controlled manner. This physiological response of the β-cell to elevated blood glucose levels is critical for maintenance of normoglycaemia and impaired Glucose stimulated insulin secretion (GSIS) is a prominent feature of overt type 2 diabetes. Thus, the identification of signals and pathways that ensure and stimulate GSIS in β-cells is of great clinical interest. Here we show (Paper I) that BMPRIA and its high affinity ligand BMP4 are expressed in fetal and adult islets. We also provide evidence that BMPRIA signaling in adult β-cell is required for GSIS, and that both transgenic expression of Bmp4 in β-cells or systemic administration of BMP4 protein to mice enhances GSIS. Thus, BMP4-BMPRIA signaling in β-cells positively regulates the genetic machinery that ensures GSIS.

    Arsenite induced ATPase (Asna1), the homologue of the bacterial ArsA ATPase, is expressed in insulin producing cells of both mammals and the nematode Caenorhabditis elegans (C.elegans). Asna1 has been proposed to act as an evolutionary conserved regulator of insulin/insulin like factor signaling. In C.elegans, asna-1 has been shown to regulate growth in a non-cell autonomous and IGF-receptor dependent manner. Here we show that transgenic expression of ASNA1 in β-cells of mice leads to enhanced Aktactivity and β-cell hyperplasia (manuscript). ASNA1 transgenic mice develop, however, diabetes due to impaired insulin secretion. The expression of genes involved in secretion stimulus coupling and insulin exocytosis is perturbed in islets of these mice. These data suggest that activation of ASNA1, here mimicked by enhanced expression, positively influences β-cell mass but negatively affects insulin secretion.

  • 47.
    Goulley, Joan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dahl, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Baeza, Nathalie
    Mishina, Yuji
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion.2007Inngår i: Cell Metabolism, ISSN 1550-4131, Vol. 5, nr 3, 207-219 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 48. Grong, Eivind
    et al.
    Kulseng, Bård
    Arbo, Ingerid Brænne
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mårvik, Ronald
    Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography2016Inngår i: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, nr 2, 532-542 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background In type 2 diabetes mellitus, there is a progressive loss of beta-cell mass. Bariatric surgery has in recent investigations showed promising results in terms of diabetes remission, but little is established regarding the effect of surgery on the survival or regeneration of pancreatic beta-cells. In this study, we aim to explore how bariatric surgery with its subsequent hormonal alterations affects the islets of Langerhans.

    Methods Twenty-four Goto-Kakizaki rats were operated with duodenojejunostomy (DJ), sleeve gastrectomy (SG) or sham operation. From the 38th week after surgery, body weight, fasting blood glucose, glycosylated hemoglobin, mixed meal tolerance with repeated measures of insulin, glucagon-like peptide 1, gastrin and total ghrelin were evaluated. Forty-six weeks after surgery, the animals were euthanized and the total beta-cell mass in all animals was examined by three-dimensional volume quantification by optical projection tomography based on the signal from insulin-specific antibody staining.

    Results Body weight did not differ between groups (Pg = 0.37). SG showed lower fasting blood glucose compared to DJ and sham (Pg = 0.037); HbA1c levels in SG were lower compared to DJ only (p\0.05). GLP-1 levels were elevated for DJ compared to SG and sham (Pg = 0.001), whereas gastrin levels were higher in SG compared to the two other groups (Pg = 0.002). Beta-cell mass was significantly greater in animals operated with SG compared to both DJ and sham (p = 0.036).

    Conclusion Sleeve gastrectomy is superior to duodenojejunostomy and sham operation when comparing the preservation of beta-cell mass 46 weeks after surgery in Goto-Kakizaki rats. This could be related to both the increased gastrin levels and the long-term improvement in glycemic parameters observed after this procedure.

  • 49.
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The lens: a classical model of embryonic induction providing new insights into cell determination in early development2011Inngår i: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, Vol. 366, nr 1568, 1193-1203 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lens was the first tissue in which the concept of embryonic induction was demonstrated. For many years lens induction was thought to occur at the time the optic vesicle and lens placode came in contact. Since then, studies have revealed that lens placodal progenitor cells are specified already at gastrula stages, much earlier than previously believed, and independent of optic vesicle interactions. In this review, I will focus on how individual signalling molecules, in particular BMP, FGF, Wnt and Shh, regulate the initial specification of lens placodal cells and the progressive development of lens cells. I will discuss recent work that has shed light on the combination of signalling molecules and the molecular interactions that affect lens specification and proper lens formation. I will also discuss proposed tissue interactions important for lens development. A greater knowledge of the molecular interactions during lens induction is likely to have practical benefits in understanding the causes and consequences of lens diseases. Moreover, knowledge regarding lens induction is providing fundamental important insights into inductive processes in development in general.

  • 50.
    Gunhaga, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Jessell, T M
    Edlund, Thomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo2000Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 127, nr 15, 3283-3293 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A secreted signaling factor, Sonic hedgehog (Shh), has a crucial role in the generation of ventral cell types along the entire rostrocaudal axis of the neural tube. At caudal levels of the neuraxis, Shh is secreted by the notochord and floor plate during the period that ventral cell fates are specified. At anterior prosencephalic levels that give rise to the telencephalon, however, neither the prechordal mesoderm nor the ventral neural tube expresses Shh at the time that the overt ventral character of the telencephalon becomes evident. Thus, the precise role and timing of Shh signaling relevant to the specification of ventral telencephalic identity remains unclear. By analysing neural cell differentiation in chick neural plate explants we provide evidence that neural cells acquire molecular properties characteristic of the ventral telencephalon in response to Shh signals derived from the anterior primitive streak/Hensen's node region at gastrula stages. Exposure of prospective anterior prosencephalic cells to Shh at this early stage is sufficient to initiate a temporal program of differentiation that parallels that of neurons generated normally in the medial ganglionic eminence subdivision of the ventral telencephalon.

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