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  • 1.
    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 neurons2012Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, nr 8, s. 3464-3472Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Hagglund, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Jones, Iwan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development2017Ingår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, nr 3, s. 245-257Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

  • 3.
    Hägglund, AC
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dahl, Lina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lhx2 is required for expansion of progenitor cells committed to eye developmentManuskript (preprint) (Övrigt vetenskapligt)
  • 4.
    Hägglund, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Berghard, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Canonical Wnt/beta-Catenin Signalling Is Essential for Optic Cup Formation2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e81158-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A multitude of signalling pathways are involved in the process of forming an eye. Here we demonstrate that beta-catenin is essential for eye development as inactivation of beta-catenin prior to cellular specification in the optic vesicle caused anophthalmia in mice. By achieving this early and tissue-specific beta-catenin inactivation we find that retinal pigment epithelium (RPE) commitment was blocked and eye development was arrested prior to optic cup formation due to a loss of canonical Wnt signalling in the dorsal optic vesicle. Thus, these results show that Wnt/beta-catenin signalling is required earlier and play a more central role in eye development than previous studies have indicated. In our genetic model system a few RPE cells could escape beta-catenin inactivation leading to the formation of a small optic rudiment. The optic rudiment contained several neural retinal cell classes surrounded by an RPE. Unlike the RPE cells, the neural retinal cells could be beta-catenin- negative revealing that differentiation of the neural retinal cell classes is beta-catenin-independent. Moreover, although dorsoventral patterning is initiated in the mutant optic vesicle, the neural retinal cells in the optic rudiment displayed almost exclusively ventral identity. Thus, beta-catenin is required for optic cup formation, commitment to RPE cells and maintenance of dorsal identity of the retina.

  • 5.
    Hägglund, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dahl, Lina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lhx2 is required for patterning and expansion of a distinct progenitor cell population committed to eye development2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 8, s. e23387-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Progenitor cells committed to eye development become specified in the prospective forebrain and develop subsequently into the optic vesicle and the optic cup. The optic vesicle induces formation of the lens placode in surface ectoderm from which the lens develops. Numerous transcription factors are involved in this process, including the eye-field transcription factors. However, many of these transcription factors also regulate the patterning of the anterior neural plate and their specific role in eye development is difficult to discern since eye-committed progenitor cells are poorly defined. By using a specific part of the Lhx2 promoter to regulate Cre recombinase expression in transgenic mice we have been able to define a distinct progenitor cell population in the forebrain solely committed to eye development. Conditional inactivation of Lhx2 in these progenitor cells causes an arrest in eye development at the stage when the optic vesicle induces lens placode formation in the surface ectoderm. The eye-committed progenitor cell population is present in the Lhx2(-/-) embryonic forebrain suggesting that commitment to eye development is Lhx2-independent. However, re-expression of Lhx2 in Lhx2(-/-) progenitor cells only promotes development of retinal pigment epithelium cells, indicating that Lhx2 promotes the acquisition of the oligopotent fate of these progenitor cells. This approach also allowed us to identify genes that distinguish Lhx2 function in eye development from that in the forebrain. Thus, we have defined a distinct progenitor cell population in the forebrain committed to eye development and identified genes linked to Lhx2’s function in the expansion and patterning of these progenitor cells.

  • 6.
    Jones, Iwan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Reduced mTORC1-signalling in retinal progenitor cells leads to visual pathway dysfunction2019Ingår i: Biology Open, ISSN 2046-6390, Vol. 8, nr 8, artikel-id bio044370Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Development of the vertebrate central nervous system involves the co-ordinated differentiation of progenitor cells and the establishment of functional neural networks. This neurogenic process is driven by both intracellular and extracellular cues that converge on the mammalian target of rapamycin complex 1 (mTORC1). Here we demonstrate that mTORC1-signalling mediates multi-faceted roles during central nervous system development using the mouse retina as a model system. Downregulation of mTORC1-signalling in retinal progenitor cells by conditional ablation of Rptor leads to proliferation deficits and an over-production of retinal ganglion cells during embryonic development. In contrast, reduced mTORC1-signalling in postnatal animals leads to temporal deviations in programmed cell death and the consequent production of asymmetric retinal ganglion cell mosaics and associated loss of axonal termination topographies in the dorsal lateral geniculate nucleus of adult mice. In combination these developmental defects induce visually mediated behavioural deficits. These collective observations demonstrate that mTORC1-signalling mediates critical roles during visual pathway development and function.

  • 7.
    Jones, Iwan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Törnqvist, Gunilla
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development2015Ingår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, nr 12, s. 1517-1529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

  • 8.
    Liu, Kui
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wahlberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Expression pattern and functional studies of matrix degrading proteases and their inhibitors in the mouse corpus luteum2003Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 205, nr 1-2, s. 131-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The formation of the corpus luteum (CL) is accompanied with angiogenesis and tissue remodeling and its regression involves tissue degradation. Matrix degrading proteases such as plasminogen activators (PAs) and matrix metalloproteinases (MMPs) are thought to play important roles in such controlled proteolytic processes. In this study, in situ hybridization has been used to examine the regulation and expression pattern of mRNAs coding for proteases and protease inhibitors belonging to the PA- and MMP-systems during the life cycle of the CL in an adult pseudopregnant mouse model. Of the nine proteases and five protease inhibitors that were studied, the majority were found to be temporally expressed during the formation and/or the regression of the CL. However, the mRNAs coding for urokinase type PA (uPA), membrane-type 1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinases type-3 (TIMP-3) were constantly expressed in the mouse CL throughout its whole life span. To study the functional role of uPA in the CL, we analyzed luteal formation and function in uPA deficient mice. Our results revealed no significant difference in ovarian weight, serum progesterone levels, and blood vessel density in the functional CL between uPA deficient and wild type control mice. The temporal and spatial expression pattern of proteases and protease inhibitors during the CL life span suggests that members of the PA- and MMP-systems may play important roles in the angiogenesis and tissue remodeling processes during CL formation, as well as in the tissue degradation during luteal regression. However, the absence of reproductive phenotypes in mice lacking uPA and several other matrix degrading proteases indicates that there are redundancies among different matrix degrading proteases or that tissue remodeling in the ovary may involve other additional unique elements.

  • 9.
    Liu, Kui
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wahlberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Leonardsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ny, Annelii
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bodén, Ida
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wibom, Carin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lund, Leif R
    Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.2006Ingår i: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 295, nr 2, s. 615-622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.

  • 10.
    Törnqvist, Gunilla
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Sandberg, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Cyclic expression of lhx2 regulates hair formation.2010Ingår i: PLoS genetics, ISSN 1553-7404, Vol. 6, nr 4, s. e1000904-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hair is important for thermoregulation, physical protection, sensory activity, seasonal camouflage, and social interactions. Hair is generated in hair follicles (HFs) and, following morphogenesis, HFs undergo cyclic phases of active growth (anagen), regression (catagen), and inactivity (telogen) throughout life. The transcriptional regulation of this process is not well understood. We show that the transcription factor Lhx2 is expressed in cells of the outer root sheath and a subpopulation of matrix cells during both morphogenesis and anagen. As the HFs enter telogen, expression becomes undetectable and reappears prior to initiation of anagen in the secondary hair germ. In contrast to previously published results, we find that Lhx2 is primarily expressed by precursor cells outside of the bulge region where the HF stem cells are located. This developmental, stage- and cell-specific expression suggests that Lhx2 regulates the generation and regeneration of hair. In support of this hypothesis, we show that Lhx2 is required for anagen progression and HF morphogenesis. Moreover, transgenic expression of Lhx2 in postnatal HFs is sufficient to induce anagen. Thus, our results reveal an alternative interpretation of Lhx2 function in HFs compared to previously published results, since Lhx2 is periodically expressed, primarily in precursor cells distinct from those in the bulge region, and is an essential positive regulator of hair formation.

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