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  • 1.
    Cumming, Joshua
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Pietras, Kristian
    Patthey, Cedric
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dissecting FAP+ mesenchymal cell diversity and regulation uncovers an interferonresponse cancer-associated fibroblast subtypeManuskript (preprint) (Övrigt vetenskapligt)
  • 2.
    Jidigam, Vijay K.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Srinivasan, Raghuraman C.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Apical constriction and epithelial invagination are regulated by BMP activity2015Ingår i: Biology open, ISSN 2046-6390, Vol. 4, nr 12, s. 1782-1791Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures through bending of the tissue. It is accompanied by apical constriction, in which the apical cell surface is reduced in relation to the basal cell surface. Although much is known about the intra-cellular molecular machinery driving apical constriction and epithelial invagination, information of how extra-cellular signals affect these processes remains insufficient. In this study we have established several in vivo assays of placodal invagination to explore whether the external signal BMP regulates processes connected to epithelial invagination. By inhibiting BMP activity in prospective cranial placodes, we provide evidence that BMP signals are required for RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination. The failure of placode invagination after BMP inhibition appears to be a direct consequence of disrupted apical accumulation of RhoA and F-actin, rather than changes in cell death or proliferation. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two distinct and separable developmental processes. In summary, our results provide evidence that BMP signals promote epithelial invagination by acting upstream of the intracellular molecular machinery that drives apical constriction and cell elongation.

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  • 3.
    Lara-Ramirez, Ricardo
    et al.
    Department of Zoology, The Tinbergen Building, University of Oxford, Oxford, United Kingdom.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Department of Zoology, The Tinbergen Building, University of Oxford, Oxford, United Kingdom.
    Shimeld, Sebastian M.
    Department of Zoology, The Tinbergen Building, University of Oxford, Oxford, United Kingdom.
    Characterization of two neurogenin genes from the brook lamprey lampetra planeri and their expression in the lamprey nervous system2015Ingår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 244, nr 9, s. 1096-1108Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Neurogenins are required for the specification of neuronal precursors and regulate the expression of basic Helix-Loop-Helix genes involved in neuronal differentiation. Jawed vertebrates possess three Neurogenin paralogy groups and their combined expression covers the entire nervous system, apart from the autonomic nervous system. Results: Here we report the isolation of two Neurogenin genes, LpNgnA and LpNgnB, from the lamprey Lampetra planeri. Phylogenetic analyses show both genes have orthologues in other lamprey species and in a hagfish. Neither gene shows evidence of orthology to specific jawed vertebrate Neurogenin paralogues. LpNgnA is expressed in the ventricular zone of regions of the brain and spinal cord, with expression in the brain demarcating brain sub-compartments including the pallium, tegmentum, tectum, and dorsal thalamus. In the peripheral nervous system, LpNgnA is expressed in cranial sensory placodes and their derivatives, and in the dorsal root ganglia. LpNgnB is expressed transiently in placodal head ectoderm and throughout the central nervous system in early development, and in a small population cells that form part of the macula. Conclusions: Combined, LpNgnA and LpNgnB were detected in most cell populations marked by Neurogenin gene expression in jawed vertebrates, with the exception of the cerebellum, retina and the non-neural expression sites. (c) 2015 Wiley Periodicals, Inc.

  • 4. Lara-Ramirez, Ricardo
    et al.
    Perez-Gonzalez, Carlos
    Anselmi, Chiara
    Patthey, Cedric
    Department of Zoology, University of Oxford, Oxford, UK.
    Shimeld, Sebastian M.
    A Notch-regulated proliferative stem cell zone in the developing spinal cord is an ancestral vertebrate trait2019Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, nr 1, artikel-id dev166595Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vertebrates have evolved the most sophisticated nervous systems we know. These differ from the nervous systems of invertebrates in several ways, including the evolution of new cell types, and the emergence and elaboration of patterning mechanisms to organise cells in time and space. Vertebrates also generally have many more cells in their central nervous systems than invertebrates, and an increase in neural cell number may have contributed to the sophisticated anatomy of the brain and spinal cord. Here, we study how increased cell number evolved in the vertebrate central nervous system, investigating the regulation of cell proliferation in the lamprey spinal cord. Markers of proliferation show that a ventricular progenitor zone is found throughout the lamprey spinal cord. We show that inhibition of Notch signalling disrupts the maintenance of this zone. When Notch is blocked, progenitor cells differentiate precociously, the proliferative ventricular zone is lost and differentiation markers become expressed throughout the spinal cord. Comparison with other chordates suggests that the emergence of a persistent Notch-regulated proliferative progenitor zone was a crucial step for the evolution of vertebrate spinal cord complexity.

  • 5. Lara-Ramirez, Ricardo
    et al.
    Poncelet, Guillaume
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
    Shimeld, Sebastian M.
    The structure, splicing, synteny and expression of lamprey COE genes and the evolution of the COE gene family in chordates2017Ingår i: Development, Genes and Evolution, ISSN 0949-944X, E-ISSN 1432-041X, Vol. 227, nr 5, s. 319-338Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    COE genes encode transcription factors that have been found in all metazoans examined to date. They possess a distinctive domain structure that includes a DNA-binding domain (DBD), an IPT/TIG domain and a helix-loop-helix (HLH) domain. An intriguing feature of the COE HLH domain is that in jawed vertebrates it is composed of three helices, compared to two in invertebrates. We report the isolation and expression of two COE genes from the brook lamprey Lampetra planeri and compare these to COE genes from the lampreys Lethenteron japonicum and Petromyzon marinus. Molecular phylogenetic analyses do not resolve the relationship of lamprey COE genes to jawed vertebrate paralogues, though synteny mapping shows that they all derive from duplication of a common ancestral genomic region. All lamprey genes encode conserved DBD, IPT/TIG and HLH domains; however, the HLH domain of lamprey COE-A genes encodes only two helices while COE-B encodes three helices. We also identified COE-B splice variants encoding either two or three helices in the HLH domain, along with other COE-A and COE-B splice variants affecting the DBD and C-terminal transactivation regions. In situ hybridisation revealed expression in the lamprey nervous system including the brain, spinal cord and cranial sensory ganglia. We also detected expression of both genes in mesenchyme in the pharyngeal arches and underlying the notochord. This allows us to establish the primitive vertebrate expression pattern for COE genes and compare this to that of invertebrate chordates and other animals to develop a model for COE gene evolution in chordates.

  • 6.
    Lidström, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Cumming, Joshua
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Gaur, Rahul
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Frängsmyr, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Pateras, Ioannis S.
    2nd Department of Pathology, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Mickert, Matthias J.
    Lumito AB, Lund, Sweden.
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dongre, Mitesh
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer2023Ingår i: Cancer immunology research, ISSN 2326-6066, Vol. 11, nr 1, s. 72-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

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  • 7.
    Lidström, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Coordination and cooperation of immunosuppressive mechanisms in pancreatic ductal adenocarcinomaManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ability to evade the immune system is crucial for cancer cells to survive. In pancreatic ductal adenocarcinoma (PDAC), various mechanisms contributing to immunosuppression have been described, including the recruitment of suppressive immune cells like M2 macrophages, the expression of cell membrane attached proteins like PDL-1, or secretion of extracellular proteins inducing immune cell apoptosis. PDAC is characterized by a rich stroma, consisting of large quantities of extracellular matrix (ECM) proteins, immune cells, fibroblasts and blood vessels. Cancer cell-derived proteins deposited in the stroma can inhibit immune cell function and thereby contribute to the progression of the disease. Galectin 4 (gal 4) is highly expressed by PDAC cancer cells and is secreted into the stroma and has recently been shown to have the capacity to induce T-cell apoptosis in PDAC tumor. High levels of gal 4 is also associated to poor prognosis and reduced immune activity in PDAC patients. Here we show that sets of immunosuppressive genes form groups based on correlation of expression levels. Gal 4 gene expression correlates with other galectin family proteins, collectively clustering into a distinct immune evasion group. This cluster has negative correlation to other more classical immunosuppressive factors, such as PDL-1, CXCL12, and TGFBI, indicating that a subset of tumors mainly relies on galectins to achieve immune evasion. Conversely, tumors with low expression of gal 4 have high expression of one or more of the classical immunosuppressive factors. These results indicate that different tumors rely on different mechanisms to achieve immune evasion and emphasize the need for personalized treatment strategies when targeting immunosuppression in PDAC.  

  • 8. Mason, James
    et al.
    Cumming, Joshua
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Eriksson, Anna U.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Binder, Carina
    Dongre, Mitesh
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Patthey, Cedric
    Espona-Fiedler, Margarita
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Potentiating the tumor-restraining properties of the stroma in pancreatic cancer with small moleculesManuskript (preprint) (Övrigt vetenskapligt)
  • 9.
    Olander, Susanne
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Nordström, Ulrika
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Patthey, Cedric
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Edlund, Thomas
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Convergent Wnt and FGF signaling at the gastrula stage induce the formation of the isthmic organizer.2006Ingår i: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 123, nr 2, s. 166-176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of the vertebrate brain depends on the formation of local organizing centres within the neural tube that express secreted signals that refine local neural progenitor identity. The isthmic organizer (IsO) forms at the isthmic constriction and is required for the growth and ordered development of mesencephalic and metencephalic structures. The formation of the IsO, which is characterized by the generation of a complex pattern of cells at the midbrain-hindbrain boundary, has been described in detail. However, when neural plate cells are initially instructed to form the IsO, the molecular nature of the inductive signals remain poorly defined. We now provide evidence that convergent Wnt and FGF signaling at the gastrula stage are required to generate the complex polarized pattern of cells characteristic of the IsO, and that Wnt and FGF signals in combination are sufficient to reconstruct, in naïve forebrain cells, an IsO-like structure that exhibits an organizing activity that mimics the endogenous IsO when transplanted into the diencephalon of chick embryos.

  • 10.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Slekiene, Lina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Extensive apoptosis during the formation of the terminal nerve ganglion by olfactory placode-derived cells with distinct molecular markers2019Ingår i: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 110, s. 8-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The terminal nerve ganglion (TNG) is a well-known structure of the peripheral nervous system in cartilaginous and teleost fishes. It derives from the olfactory placode during embryonic development. While the differentiation and migration of gonadotropin releasing hormone (GnRH)-expressing neurons from the olfactory placode has been well documented, the TNG has been neglected in birds and mammals, and its development is less well described. Here we describe the formation of a ganglion-like structure from migratory olfactory placodal cells in chicken. The TNG is surrounded by neural crest cells, but in contrast to other cranial sensory ganglia, we observed no neural crest corridor, and olfactory unsheathing cells appear only after the onset of neuronal migration. We identified Isl1 and Lhx2 as two transcription factors that label neuronal subpopulations in the forming TNG, distinct from GnRH1(+) cells, thereby revealing a diversity of cell types during the formation of the TNG. We also provide evidence for extensive apoptosis in the terminal nerve ganglion shortly after its formation, but not in other cranial sensory ganglia. Moreover, at later stages placode-derived neurons expressing GnRH1, Isl1 and/or Lhx2 become incorporated in the telencephalon. The integration of TNG neurons into the telencephalon together with the earlier widespread apoptosis in the TNG might be an explanation why the TNG in mammals and birds is much smaller compared to other vertebrates.

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  • 11.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Wittmann, Walter
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Jidigam, Vijay K.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mercurio, Sara
    Bertolini, Jessica A.
    Sghari, Soufien
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Bose, Raj
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nicolis, Silvia K.
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation2018Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, nr 2, artikel-id dev153791Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transcription factor Sox2 is necessary to maintain pluripotency of embryonic stem cells, and to regulate neural development. Neurogenesis in the vertebrate olfactory epithelium persists from embryonic stages through adulthood. The role Sox2 plays for the development of the olfactory epithelium and neurogenesis within has, however, not been determined. Here, by analysing Sox2 conditional knockout mouse embryos and chick embryos deprived of Sox2 in the olfactory epithelium using CRISPR-Cas9, we show that Sox2 activity is crucial for the induction of the neural progenitor gene Hes5 and for subsequent differentiation of the neuronal lineage. Our results also suggest that Sox2 activity promotes the neurogenic domain in the nasal epithelium by restricting Bmp4 expression. The Sox2-deficient olfactory epithelium displays diminished cell cycle progression and proliferation, a dramatic increase in apoptosis and finally olfactory pit atrophy. Moreover, chromatin immunoprecipitation data show that Sox2 directly binds to the Hes5 promoter in both the PNS and CNS. Taken together, our results indicate that Sox2 is essential to establish, maintain and expand the neuronal progenitor pool by suppressing Bmp4 and upregulating Hes5 expression.

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  • 12.
    Pandit, Tanushree
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Jidigam, Vijay Kumar
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Neural retina identity is specified by lens-derived BMP signals2015Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 142, nr 10, s. 1850-1859Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity.

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  • 13.
    Papadogiannis, Vasileios
    et al.
    Department of Biology, University of Oxford, Oxford, United Kingdom.
    Hockman, Dorit
    Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Neuroscience Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
    Mercurio, Silvia
    Department of Environmental Science and Policy, Università Degli Studi di Milano, Milano, Italy.
    Ramsay, Claire
    Department of Biology, University of Oxford, 1Oxford, United Kingdom.
    Hintze, Mark
    Centre for Craniofacial & Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Streit, Andrea
    Centre for Craniofacial & Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom.
    Shimeld, Sebastian M.
    Department of Biology, University of Oxford, Oxford, United Kingdom.
    Evolution of the expression and regulation of the nuclear hormone receptor ERR gene family in the chordate lineage2023Ingår i: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 504, s. 12-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Estrogen Related Receptor (ERR) nuclear hormone receptor genes have a wide diversity of roles in vertebrate development. In embryos, ERR genes are expressed in several tissues, including the central and peripheral nervous systems. Here we seek to establish the evolutionary history of chordate ERR genes, their expression and their regulation. We examine ERR expression in mollusc, amphioxus and sea squirt embryos, finding the single ERR orthologue is expressed in the nervous system in all three, with muscle expression also found in the two chordates. We show that most jawed vertebrates and lampreys have four ERR paralogues, and that vertebrate ERR genes were ancestrally linked to Estrogen Receptor genes. One of the lamprey paralogues shares conserved expression domains with jawed vertebrate ERRγ in the embryonic vestibuloacoustic ganglion, eye, brain and spinal cord. Hypothesising that conserved expression derives from conserved regulation, we identify a suite of pan-vertebrate conserved non-coding sequences in ERR introns. We use transgenesis in lamprey and chicken embryos to show that these sequences are regulatory and drive reporter gene expression in the nervous system. Our data suggest an ancient association between ERR and the nervous system, including expression in cells associated with photosensation and mechanosensation. This includes the origin in the vertebrate common ancestor of a suite of regulatory elements in the 3’ introns that drove nervous system expression and have been conserved from this point onwards.

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  • 14.
    Papadogiannis, Vasileios
    et al.
    Department of Zoology, University of Oxford, Oxford, United Kingdom; Institute of Marine Biology, Biotechnology and Aquaculture, Hellenic Centre for Marine Research, Gournes, Crete, Greece.
    Pennati, Alessandro
    Department of Zoology, University of Oxford, Oxford, United Kingdom; Institute of Zoology and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
    Parker, Hugo J.
    Stowers Institute for Medical Research, MO, Kansas City, United States.
    Rothbächer, Ute
    Institute of Zoology and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bronner, Marianne E.
    Division of Biology and Biological Engineering, California Institute of Technology, CA, Pasadena, United States.
    Shimeld, Sebastian M.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Hmx gene conservation identifies the origin of vertebrate cranial ganglia2022Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 605, nr 7911, s. 701-705Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The evolutionary origin of vertebrates included innovations in sensory processing associated with the acquisition of a predatory lifestyle1. Vertebrates perceive external stimuli through sensory systems serviced by cranial sensory ganglia, whose neurons arise predominantly from cranial placodes; however, the understanding of the evolutionary origin of placodes and cranial sensory ganglia is hampered by the anatomical differences between living lineages and the difficulty in assigning homology between cell types and structures. Here we show that the homeobox transcription factor Hmx is a constitutive component of vertebrate sensory ganglion development and that in the tunicate Ciona intestinalis, Hmx is necessary and sufficient to drive the differentiation programme of bipolar tail neurons, cells previously thought to be homologues of neural crest2,3. Using Ciona and lamprey transgenesis, we demonstrate that a unique, tandemly duplicated enhancer pair regulated Hmx expression in the stem-vertebrate lineage. We also show notably robust vertebrate Hmx enhancer function in Ciona, demonstrating that deep conservation of the upstream regulatory network spans the evolutionary origin of vertebrates. These experiments demonstrate regulatory and functional conservation between Ciona and vertebrate Hmx, and point to bipolar tail neurons as homologues of cranial sensory ganglia.

  • 15.
    Patthey, Cedric
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Department of Zoology, University of Oxford, Oxford, UK.
    Clifford, Harry
    Haerty, Wilfried
    Ponting, Chris P.
    Shimeld, Sebastian M.
    Begbie, Jo
    Identification of molecular signatures specific for distinct cranial sensory ganglia in the developing chick2016Ingår i: Neural Development, ISSN 1749-8104, Vol. 11, artikel-id 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The cranial sensory ganglia represent populations of neurons with distinct functions, or sensory modalities. The production of individual ganglia from distinct neurogenic placodes with different developmental pathways provides a powerful model to investigate the acquisition of specific sensory modalities. To date there is a limited range of gene markers available to examine the molecular pathways underlying this process.

    Results: Transcriptional profiles were generated for populations of differentiated neurons purified from distinct cranial sensory ganglia using microdissection in embryonic chicken followed by FAC-sorting and RNAseq. Whole transcriptome analysis confirmed the division into somato- versus viscerosensory neurons, with additional evidence for subdivision of the somatic class into general and special somatosensory neurons. Cross-comparison of distinct ganglia transcriptomes identified a total of 134 markers, 113 of which are novel, which can be used to distinguish trigeminal, vestibulo-acoustic and epibranchial neuronal populations. In situ hybridisation analysis provided validation for 20/26 tested markers, and showed related expression in the target region of the hindbrain in many cases.

    Conclusions: One hundred thirty-four high-confidence markers have been identified for placode-derived cranial sensory ganglia which can now be used to address the acquisition of specific cranial sensory modalities.

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  • 16.
    Patthey, Cedric
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Signaling pathways regulating ectodermal cell fate choices2014Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 321, nr 1, s. 11-16Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Although embryonic patterning and early development of the nervous system have been studied for decades, our understanding of how signals instruct ectodermal derivatives to acquire specific identities has only recently started to form a coherent picture. In this mini-review, we summarize recent findings and models of how a handful of well-known secreted signals influence progenitor cells in successive binary decisions to adopt various cell type specific differentiation programs.

  • 17.
    Patthey, Cedric
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Specification and regionalisation of the neural plate border2011Ingår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 34, nr 10, s. 1516-1528Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During early vertebrate development, the embryonic ectoderm becomes subdivided into neural, neural plate border (border) and epidermal regions. The nervous system is derived from the neural and border domains which, respectively, give rise to the central and peripheral nervous systems. To better understand the functional nervous system we need to know how individual neurons are specified and connected. Our understanding of the early development of the peripheral nervous system has been lagging compared to knowledge regarding central nervous system and epidermal cell lineage decision. Recent advances have shown when and how the specification of border cells is initiated. One important insight is that border specification is already initiated at blastula stages, and can be molecularly and temporally distinguished from rostrocaudal regionalisation of the border. From findings in several species, it is clear that Wnt, Bone Morphogenetic Protein and Fibroblast Growth Factor signals play important roles during the specification and regionalisation of the border. In this review, we highlight the individual roles of these signals and compare models of border specification, including a new model that describes how temporal coordination and epistatic interactions of extracellular signals result in the specification and regionalisation of border cells.

  • 18.
    Patthey, Cedric
    et al.
    Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
    Schlosser, Gerhard
    Zoology, School of Natural Sciences & Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, University Road, Galway, Ireland.
    Shimeld, Sebastian M.
    Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
    The evolutionary history of vertebrate cranial placodes - I: Cell type evolution2014Ingår i: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 389, nr 1, s. 82-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vertebrate cranial placodes are crucial contributors to the vertebrate cranial sensory apparatus. Their evolutionary origin has attracted much attention from evolutionary and developmental biologists, yielding speculation and hypotheses concerning their putative homologues in other lineages and the developmental and genetic innovations that might have underlain their origin and diversification. In this article we first briefly review our current understanding of placode development and the cell types and structures they form. We next summarise previous hypotheses of placode evolution, discussing their strengths and caveats, before considering the evolutionary history of the various cell types that develop from placodes. In an accompanying review, we also further consider the evolution of ectodermal patterning. Drawing on data from vertebrates, tunicates, amphioxus, other bilaterians and cnidarians, we build these strands into a scenario of placode evolutionary history and of the genes, cells and developmental processes that underlie placode evolution and development. (C) 2014 Elsevier Inc. All rights reserved.

  • 19.
    Patthey, Cedric
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Tong, Yong Guang
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Tait, Christine Mary
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Wilson, Sara Ivy
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Evolution of the functionally conserved DCC gene in birds2017Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 42029Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding the loss of conserved genes is critical for determining how phenotypic diversity is generated. Here we focus on the evolution of DCC, a gene that encodes a highly conserved neural guidance receptor. Disruption of DCC in animal models and humans results in major neurodevelopmental defects including commissural axon defects. Here we examine DCC evolution in birds, which is of particular interest as a major model system in neurodevelopmental research. We found the DCC containing locus was disrupted several times during evolution, resulting in both gene losses and faster evolution rate of salvaged genes. These data suggest that DCC had been lost independently twice during bird evolution, including in chicken and zebra finch, whereas it was preserved in many other closely related bird species, including ducks. Strikingly, we observed that commissural axon trajectory appeared similar regardless of whether DCC could be detected or not. We conclude that the DCC locus is susceptible to genomic instability leading to independent disruptions in different branches of birds and a significant influence on evolution rate. Overall, the phenomenon of loss or molecular evolution of a highly conserved gene without apparent phenotype change is of conceptual importance for understanding molecular evolution of key biological processes.

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  • 20.
    Patthey, Cédric
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Edlund, Thomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gunhaga, Lena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Wnt-regulated temporal control of BMP exposure directs the choice between neural plate border and epidermal fate2009Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 136, nr 1, s. 73-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The non-neural ectoderm is divided into neural plate border and epidermal cells. At early blastula stages, Wnt and BMP signals interact to induce epidermal fate, but when and how cells initially acquire neural plate border fate remains poorly defined. We now provide evidence in chick that the specification of neural plate border cells is initiated at the late blastula stage and requires both Wnt and BMP signals. Our results indicate, however, that at this stage BMP signals can induce neural plate border cells only when Wnt activity is blocked, and that the two signals in combination generate epidermal cells. We also provide evidence that Wnt signals do not play an instructive role in the generation of neural plate border cells, but promote their generation by inducing BMP gene expression, which avoids early simultaneous exposure to the two signals and generates neural plate border instead of epidermal cells. Thus, specification of neural plate border cells is mediated by a novel Wnt-regulated BMP-mediated temporal patterning mechanism.

  • 21.
    Signoret, Carine
    et al.
    Linnaeus Centre HEAD, Swedish Institute for Disability Research, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Ng, Elaine
    Linnaeus Centre HEAD, Swedish Institute for Disability Research, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Da Silva, Stéphanie
    Department of Clinical and Experimental Medicine, Division of Surgery, Faculty of Health Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden.
    Tack, Ayco
    Department of Ecology, Environment and Plant Sciences, Stockholm University, Stockholm, Sweden.
    Voss, Ulrikke
    Department of Experimental Medical Sciences, Future Faculty, Lund University, Lund, Sweden.
    Lidö, Helga H.
    Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Hadrevi, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Balachandran, Chanchal
    Department of Management and Engineering (IEI), The Institute for Analytical Sociology, Linköping University, Linköping, Sweden.
    Well-being of early-career researchers: insights from a Swedish survey2019Ingår i: Higher Education Policy, ISSN 0952-8733, E-ISSN 1740-3863, Vol. 32, nr 2, s. 273-296Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several studies have documented the importance of optimal work situation and the general well-being of early-career researchers (ECRs) for enhancing the academic performance of universities. Yet, most studies focused on specific categories of ECRs, or on specific academic disciplines as well as on specific outcomes. With this study, we recognize the need for a broader sample encompassing different categories of ECRs across academic disciplines. In a national survey of Swedish universities, the National Junior Faculty of Sweden (NJF) collected data from ECRs in order to study the influence of work situation and well-being on perceived scientific environment. We observed that work situation and well-being are interdependent and jointly influence each other in shaping the conditions for ideal scientific environment. Importantly, we employ structural equation model (SEM) analysis to account for the endogenous relationship between work situation and personal well-being in predicting perceived scientific environment. Results from SEM indicate that support from the university, work time management, job clarity, contract length and quality of life satisfaction were related to the perceived possibility of conducting the best science. Our research also highlighted individual differences across demographic factors and contract length in the perceived work situation and the possibility of conducting the best science.

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