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  • 1.
    Baek, Sungmin
    et al.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Oh, Tae Gyu
    Univ Queensland, Inst Mol Biosci, Div Cell Biol & Mol Med, Brisbane, Qld 4073, Australia.
    Secker, Genevieve
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Sutton, Drew L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Okuda, Kazuhide S.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Paterson, Scott
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Bower, Neil I.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Toubia, John
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia;Univ South Australia, Ctr Canc Biol, Fdn Canc Genom Facil, Australian Canc Res, Frome Rd, Adelaide, SA 5000, Australia.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Capon, Samuel J.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Baillie, Gregory J.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Simons, Cas
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia;Murdoch Childrens Res Inst, Parkville, Vic, Australia.
    Muscat, George E. O.
    Univ Queensland, Inst Mol Biosci, Div Cell Biol & Mol Med, Brisbane, Qld 4073, Australia.
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Smith, Kelly A.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Harvey, Natasha L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage2019In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 49, no 2, p. 279-292Article in journal (Refereed)
    Abstract [en]

    The correct assignment of cell fate within fields of multipotent progenitors is essential for accurate tissue diversification. The first lymphatic vessels arise from pre-existing veins after venous endothelial cells become specified as lymphatic progenitors. Prox1 specifies lymphatic fate and labels these progenitors; however, the mechanisms restricting Prox1 expression and limiting the progenitor pool remain unknown. We identified a zebrafish mutant that displayed premature, expanded, and prolonged lymphatic specification. The gene responsible encodes the regulator of alternative splicing, Nova2. In zebrafish and human endothelial cells, Nova2 selectively regulates pre-mRNA splicing for components of signaling pathways and phosphoproteins. Nova2-deficient endothelial cells display increased Mapk/Erk signaling, and Prox1 expression is dynamically controlled by Erk signaling. We identify a mechanism whereby Nova2-regulated splicing constrains Erk signaling, thus limiting lymphatic progenitor cell specification. This identifies the capacity of a factor that tunes mRNA splicing to control assignment of cell fate during vascular differentiation.

  • 2. Bazigou, Eleni
    et al.
    Xie, Sherry
    Chen, Chun
    Weston, Anne
    Miura, Naoyuki
    Sorokin, Lydia
    Adams, Ralf
    Muro, Andrés F
    Sheppard, Dean
    Makinen, Taija
    Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.2009In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 17, no 2Article in journal (Refereed)
    Abstract [en]

    Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-alpha9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-alpha9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-alpha9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.

  • 3. Benton, Jeanne
    et al.
    Kery, Rachel
    Li, Jingjing
    Noonin, Chadanat
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Irene
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Beltz, Barbara
    Cells from the Immune System Generate Adult-Born Neurons in Crayfish2014In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 30, no 3, p. 322-333Article in journal (Refereed)
    Abstract [en]

    Neurogenesis is an ongoing process in the brains of adult decapod crustaceans. However, the first-generation precursors that produce adult-born neurons, which reside in a neurogenic niche, are not self-renewing in crayfish and must be replenished. The source of these neuronal precursors is unknown. Here, we report that adult-born neurons in crayfish can be derived from hemocytes. Following adoptive transfer of 5-ethynyl-2′-deoxyuridine (EdU)-labeled hemocytes, labeled cells populate the neurogenic niche containing the first-generation neuronal precursors. Seven weeks after adoptive transfer, EdU-labeled cells are located in brain clusters 9 and 10 (where adult-born neurons differentiate) and express appropriate neurotransmitters. Moreover, the number of cells composing the neurogenic niche in crayfish is tightly correlated with total hemocyte counts (THCs) and can be manipulated by raising or lowering THC. These studies identify hemocytes as a source of adult-born neurons in crayfish and demonstrate that the immune system is a key contributor to adult neurogenesis.

  • 4.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Rulands, Steffen
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Dudczig, Stefanie
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Simons, Benjamin D.
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Harris, William A.
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 34, no 5, p. 532-543Article in journal (Refereed)
    Abstract [en]

    Early retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable.

  • 5. Gaengel, Konstantin
    et al.
    Niaudet, Colin
    Hagikura, Kazuhiro
    Siemsen, Barbara Lavina
    Muhl, Lars
    Hofmann, Jennifer J.
    Ebarasi, Lwaki
    Nystrom, Staffan
    Rymo, Simin
    Chen, Long Long
    Pang, Mei-Fong
    Jin, Yi
    Raschperger, Elisabeth
    Roswall, Pernilla
    Schulte, Doerte
    Benedito, Rui
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Fuxe, Jonas
    Uhlen, Per
    Adams, Ralf
    Jakobsson, Lars
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vestweber, Dietmar
    Uv, Anne
    Betsholtz, Christer
    The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR22012In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 587-599Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

  • 6.
    Heldin, Carl-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    A new twist in Smad signaling2006In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 10, no 6, p. 685-686Article in journal (Other academic)
    Abstract [en]

    Signaling by members of the TGFbeta family is much dependent on the common-mediator Smad4, which forms transcriptionally active complexes with all receptor-activated Smads (R-Smads). New findings demonstrate that transcriptional intermediary factor 1gamma (TIF1gamma) also can bind to R-Smads, as an alternative to Smad4, and mediate different transcriptional effects.

  • 7.
    Hopkins, Sarah
    et al.
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Linderoth, Emma
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Hantschel, Oliver
    CeMM – Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
    Suarez-Henriques, Paula
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Pilia, Giulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kendrick, Howard
    Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
    Smalley, Matthew J
    Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
    Superti-Furga, Giulio
    CeMM – Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
    Ferby, Ingvar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mig6 Is a Sensor of EGF Receptor Inactivation that Directly Activates c-Abl to Induce Apoptosis during Epithelial Homeostasis.2012In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 547-559Article in journal (Refereed)
    Abstract [en]

    A fundamental aspect of epithelial homeostasis is the dependence on specific growth factors for cell survival, yet the underlying mechanisms remain obscure. We found an "inverse" mode of receptor tyrosine kinase signaling that directly links ErbB receptor inactivation to the induction of apoptosis. Upon ligand deprivation Mig6 dissociates from the ErbB receptor and binds to and activates the tyrosine kinase c-Abl to trigger p73-dependent apoptosis in mammary epithelial cells. Deletion of Errfi1 (encoding Mig6) and inhibition or RNAi silencing of c-Abl causes impaired apoptosis and luminal filling of mammary ducts. Mig6 activates c-Abl by binding to the kinase domain, which is prevented in the presence of epidermal growth factor (EGF) by Src family kinase-mediated phosphorylation on c-Abl-Tyr488. These results reveal a receptor-proximal switch mechanism by which Mig6 actively senses EGF deprivation to directly activate proapoptotic c-Abl. Our findings challenge the common belief that deprivation of growth factors induces apoptosis passively by lack of mitogenic signaling.

  • 8.
    Jakobsson, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Holmborn, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis2006In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 10, no 5, p. 625-634Article in journal (Refereed)
    Abstract [en]

    Several receptor tyrosine kinases require heparan sulfate proteoglycans (HSPGs) as coreceptors for efficient signal transduction. We have studied the role of HSPGs in the development of blood capillary structures from embryonic stem cells, a process strictly dependent on signaling via vascular endothelial growth factor receptor-2 (VEGFR-2). We show, by using chimeric cultures of embryonic stem cells defective in either HS production or VEGFR-2 synthesis, that VEGF signaling in endothelial cells is fully supported by HS expressed in trans by adjacent perivascular smooth muscle cells. Transactivation of VEGFR-2 leads to prolonged and enhanced signal transduction due to HS-dependent trapping of the active VEGFR-2 signaling complex. Our data imply that direct signaling via HSPG core proteins is dispensable for a functional VEGF response in endothelial cells. We propose that transactivation of tyrosine kinase receptors by HSPGs constitutes a mechanism for crosstalk between adjacent cells.

  • 9.
    Koch, Sina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Meeteren, Laurens A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morin, Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testini, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Björkelund, Hanna
    Le Jan, Sebastien
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berger, Philipp
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation2014In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 28, no 6, p. 633-646Article in journal (Refereed)
    Abstract [en]

    Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase C gamma (PLC gamma) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.

  • 10. Kok, Fatma O.
    et al.
    Shin, Masahiro
    Ni, Chih-Wen
    Gupta, Ankit
    Grosse, Ann S.
    van Impel, Andreas
    Kirchmaier, Bettina C.
    Peterson-Maduro, Josi
    Kourkoulis, George
    Male, Ira
    DeSantis, Dana F.
    Sheppard-Tindell, Sarah
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Schulte-Merker, Stefan
    Wolfe, Scot A.
    Lawson, Nathan D.
    Reverse Genetic Screening Reveals Poor Correlation between Morpholino-Induced and Mutant Phenotypes in Zebrafish2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 32, no 1, p. 97-108Article in journal (Refereed)
    Abstract [en]

    The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site-specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses.

  • 11.
    Koskiniemi, Sanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arming the Neighborhood2016In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 39, no 1, p. 5-6Article in journal (Other academic)
    Abstract [en]

    Bacteria use type 6 secretion systems in antagonistic behavior to compete for resources with other bacteria. In a recent issue of Cell, Vettiger and Basler (2016) show that bacteria can also use these systems to arm neighboring cells and force them to pass on a signal in the bacterial population.

  • 12. Kradolfer, David
    et al.
    Wolff, Philip
    Jiang, Hua
    Siretskiy, Alexey
    Köhler, Claudia
    An imprinted gene underlies postzygotic reproductive isolation in Arabidopsis thaliana2013In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 26, no 5, p. 525-35Article in journal (Refereed)
    Abstract [en]

    Postzygotic reproductive isolation in response to interploidy hybridizations is a well-known phenomenon in plants that forms a major path for sympatric speciation. A main determinant for the failure of interploidy hybridizations is the endosperm, a nutritious tissue supporting embryo growth, similar to the functional role of the placenta in mammals. Although it has been suggested that deregulated imprinted genes underpin dosage sensitivity of the endosperm, the molecular basis for this phenomenon remained unknown. In a genetic screen for suppressors of triploid seed abortion, we have identified the paternally expressed imprinted gene ADMETOS (ADM). Here, we present evidence that increased dosage of ADM causes triploid seed arrest. A large body of theoretical work predicted that deregulated imprinted genes establish the barrier to interploidy hybridization. Our study thus provides evidence strongly supporting this hypothesis and generates the molecular basis for our understanding of postzygotic hybridization barriers in plants.

  • 13.
    Kreuger, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perez, Lidia
    Giraldez, Antonio J
    Cohen, Stephen M
    Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity.2004In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 7, no 4, p. 503-512Article in journal (Refereed)
    Abstract [en]

    The glypican family of heparan sulfate proteoglycans has been implicated in formation of morphogen gradients. Here, we examine the role of the glypican Dally-like protein (Dlp) in shaping the Wingless gradient in the Drosophila wing disc. Surprisingly, we find that Dlp has opposite effects at high and low levels of Wingless. Dlp promotes low-level Wingless activity but reduces high-level Wingless activity. We present evidence that the Wg antagonist Notum acts to induce cleavage of the Dlp glypican at the level of its GPI anchor, which leads to shedding of Dlp. Thus, spatially regulated modification of Dlp by Notum employs the ligand binding activity of Dlp to promote or inhibit signaling in a context-dependent manner. Notum-induced shedding of Dlp could convert Dlp from a membrane-tethered coreceptor to a secreted antagonist.

  • 14.
    Li, Shuijie
    et al.
    Ludwig Inst Canc Res Ltd, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol & Tumor & Cell Biol, S-17177 Stockholm, Sweden..
    Fell, Stuart M.
    Ludwig Inst Canc Res Ltd, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Surova, Olga
    Ludwig Inst Canc Res Ltd, S-17177 Stockholm, Sweden..
    Smedler, Erik
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Wallis, Karin
    Ludwig Inst Canc Res Ltd, S-17177 Stockholm, Sweden..
    Chen, Zhi Xiong
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore..
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Johnsen, John Inge
    Karolinska Inst, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden..
    Martinsson, Tommy
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Biomed, Dept Clin Genet, S-41345 Gothenburg, Sweden..
    Kenchappa, Rajappa S.
    H Lee Moffitt Canc Ctr & Res Inst, Neurooncol Program, 12902 USF Magnolia Dr, Tampa, FL 33612 USA..
    Uhlen, Per
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Kogner, Per
    Karolinska Inst, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden..
    Schlisio, Susanne
    Ludwig Inst Canc Res Ltd, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol & Tumor & Cell Biol, S-17177 Stockholm, Sweden..
    The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis2016In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 36, no 2, p. 164-178Article in journal (Refereed)
    Abstract [en]

    KIF1B beta is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1B beta activates the Ca2+-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca2+ signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1B beta affects mitochondria! dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondria! fission and apoptosis. Furthermore, KIF1B beta actuates recognition of all known CN substrates, implying a general mechanism for KIF1B beta in Ca2+ signaling and how Ca2+-dependent signaling is executed by CN. Pathogenic KIF1B beta mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1B beta and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondria! dynamics contributes to high-risk and poor-prognosis neuroblastoma.

  • 15.
    Majda, Mateusz
    et al.
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, UPSC, S-90183 Umea, Sweden..
    Grones, Peter
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, UPSC, S-90183 Umea, Sweden..
    Sintorn, Ida-Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vain, Thomas
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, UPSC, S-90183 Umea, Sweden..
    Milani, Pascale
    Univ Lyon, ENS Lyon, UCB Lyon 1, Lab Reprod & Dev Plantes,CNRS,INRA, F-69342 Lyon, France..
    Krupinski, Pawel
    Lund Univ, Dept Astron & Theoret Phys, Computat Biol & Biol Phys, Solvegatan 14A, S-22362 Lund, Sweden..
    Zagorska-Marek, Beata
    Univ Wroclaw, Inst Expt Biol, Dept Plant Dev Biol, Kanonia 6-8, PL-50328 Wroclaw, Poland..
    Viotti, Corrado
    Umea Univ, Dept Plant Physiol, UPSC, S-90187 Umea, Sweden.;Univ Potsdam, Inst Biochem & Biol, Plant Physiol, D-14476 Potsdam, Germany..
    Jonsson, Henrik
    Lund Univ, Dept Astron & Theoret Phys, Computat Biol & Biol Phys, Solvegatan 14A, S-22362 Lund, Sweden.;Univ Cambridge, Sainsbury Lab, Bateman St, Cambridge CB2 1LR, England.;Univ Cambridge, Dept Math & Theoret Phys, Cambridge CB3 0WA, England..
    Mellerowicz, Ewa J.
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, UPSC, S-90183 Umea, Sweden..
    Hamant, Olivier
    Univ Lyon, ENS Lyon, UCB Lyon 1, Lab Reprod & Dev Plantes,CNRS,INRA, F-69342 Lyon, France..
    Robert, Stephanie
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, UPSC, S-90183 Umea, Sweden..
    Mechanochemical Polarization of Contiguous Cell Walls Shapes Plant Pavement Cells2017In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 3, p. 290-304Article in journal (Refereed)
    Abstract [en]

    The epidermis of aerial plant organs is thought to be limiting for growth, because it acts as a continuous load-bearing layer, resisting tension. Leaf epidermis contains jigsaw puzzle piece-shaped pavement cells whose shape has been proposed to be a result of subcellular variations in expansion rate that induce local buckling events. Paradoxically, such local compressive buckling should not occur given the tensile stresses across the epidermis. Using computational modeling, we show that the simplest scenario to explain pavement cell shapes within an epidermis under tension must involve mechanical wall heterogeneities across and along the anticlinal pavement cell walls between adjacent cells. Combining genetics, atomic force microscopy, and immunolabeling, we demonstrate that contiguous cell walls indeed exhibit hybrid mechanochemical properties. Such biochemical wall heterogeneities precede wall bending. Altogether, this provides a possible mechanism for the generation of complex plant cell shapes.

  • 16.
    Marques, Sueli
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    van Bruggen, David
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Vanichkina, Darya Pavlovna
    Univ Sydney, Centenary Inst, Gene & Stem Cell Therapy Program, Camperdown, NSW 2050, Australia;Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4067, Australia.
    Floriddia, Elisa Mariagrazia
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Munguba, Hermany
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Väremo, Leif
    Chalmers Univ Technol, Dept Biol & Biol Engn, Sci Life Lab, Kemivagen 10, S-41296 Gothenburg, Sweden.
    Giacomello, Stefania
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Falcao, Ana Mendanha
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Meijer, Mandy
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Björklund, Åsa K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hjerling-Leffler, Jens
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Taft, Ryan James
    Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4067, Australia;Illumina Inc, San Diego, CA 92122 USA.
    Castelo-Branco, Goncalo
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development2018In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 46, no 4, p. 504-517Article in journal (Refereed)
    Abstract [en]

    Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different oligodendrocyte (OL) states at adult stages. Here, we present bulk and single-cell transcriptomics resources providing insights on how transitions between these states occur. We found that post-natal OPCs from brain and spinal cord present similar transcriptional signatures. Moreover, post-natal OPC progeny of E13.5 Pdgfra+ cells present electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves, indicating that Pdgfra+ pre-OPCs rewire their transcriptional network during development. Single-cell RNA-seq and lineage tracing indicates that a subset of E13.5 Pdgfra+ cells originates cells of the pericyte lineage. Thus, our results indicate that embryonic Pdgfra+ cells in the CNS give rise to distinct post-natal cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions.

  • 17.
    Marsit, Souhir
    et al.
    Univ Laval, IBIS, Dept Biol, PROTEO, Quebec City, PQ, Canada.
    Dion-Côté, Anne-Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA.
    Barbash, Daniel A.
    Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA.
    Did Mitochondria Kill the Frog?2018In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 44, no 5, p. 539-541Article in journal (Other academic)
    Abstract [en]

    Genomic divergence can cause reproductive isolation between species. The molecular mechanisms underlying reproductive isolation can thus reveal which genomic features evolve rapidly and become unstable or incompatible in hybrids. In a recent paper in Nature, Gibeaux et al. (2018) report paternal genome instability and metabolic imbalance in hybrids between frog species.

  • 18.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    TGF-beta Targets PAX3 to Control Melanocyte Differentiation2008In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 15, no 6, p. 797-799Article in journal (Other academic)
    Abstract [en]

    In the absence of UV radiation, keratinocytes secrete TGF-beta which blocks melanocyte differentiation. Yang et al. (2008), in a recent issue of Molecular Cell, show that TGF-beta induces Smad signaling in melanocytes to repress PAX3, which encodes a transcription factor crucial for melanocyte differentiation. In the presence of UV radiation, a Jnk/AP-1 pathway represses TGF-beta, which together with a UV-induced p53 pathway promotes melanocyte differentiation.

  • 19. Reyahi, Azadeh
    et al.
    Nik, Ali M.
    Ghiami, Mozhgan
    Gritli-Linde, Amel
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Johansson, Bengt R.
    Carlsson, Peter
    Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 34, no 1, p. 19-32Article in journal (Refereed)
    Abstract [en]

    Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2(-/-) embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2(-/-) brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfr beta. Tgf beta-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgf beta pathway components, including Tgf beta 2, Tgf beta r2, Alk5, and integrins alpha(V)beta(8), were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.

  • 20. Sabine, Amélie
    et al.
    Agalarov, Yan
    Maby-El Hajjami, Hélène
    Jaquet, Muriel
    Hägerling, René
    Pollmann, Cathrin
    Bebber, Damien
    Pfenniger, Anna
    Miura, Naoyuki
    Dormond, Olivier
    Calmes, Jean-Marie
    Adams, Ralf H
    Mäkinen, Taija
    Kiefer, Friedemann
    Kwak, Brenda R
    Petrova, Tatiana V
    Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation.2012In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 22, no 2Article in journal (Refereed)
    Abstract [en]

    Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction.

  • 21. Tatin, Florence
    et al.
    Taddei, Andrea
    Weston, Anne
    Fuchs, Elaine
    Devenport, Danelle
    Tissir, Fadel
    Makinen, Taija
    Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis.2013In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 26, no 1Article in journal (Refereed)
    Abstract [en]

    Planar cell polarity (PCP) signaling controls tissue morphogenesis by coordinating collective cell behaviors. We show a critical role for the core PCP proteins Celsr1 and Vangl2 in the complex morphogenetic process of intraluminal valve formation in lymphatic vessels. We found that valve-forming endothelial cells undergo elongation, reorientation, and collective migration into the vessel lumen as they initiate valve leaflet formation. During this process, Celsr1 and Vangl2 are recruited from endothelial filopodia to discrete membrane domains at cell-cell contacts. Celsr1- or Vangl2-deficient mice show valve aplasia due to failure of endothelial cells to undergo rearrangements and adopt perpendicular orientation at valve initiation sites. Mechanistically, we show that Celsr1 regulates dynamic cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions. These findings reveal a role for PCP signaling in regulating adherens junctions and directed cell rearrangements during vascular development.

  • 22. Vaten, Anne
    et al.
    Dettmer, Jan
    Wu, Shuang
    Stierhof, York-Dieter
    Miyashima, Shunsuke
    Yadav, Shri Ram
    Roberts, Christina J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany.
    Campilho, Ana
    Bulone, Vincent
    Lichtenberger, Raffael
    Lehesranta, Satu
    Mahonen, Ari Pekka
    Kim, Jae-Yean
    Jokitalo, Eija
    Sauer, Norbert
    Scheres, Ben
    Nakajima, Keiji
    Carlsbecker, Annelie
    Gallagher, Kimberly L.
    Helariutta, Yka
    Callose Biosynthesis Regulates Symplastic Trafficking during Root Development2011In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 21, no 6, p. 1144-1155Article in journal (Refereed)
    Abstract [en]

    Plant cells are connected through plasmodesmata (PD), membrane-lined channels that allow symplastic movement of molecules between cells. However, little is known about the role of PD-mediated signaling during plant morphogenesis. Here, we describe an Arabidopsis gene, CALS3/GSL12. Gain-of-function mutations in CALS3 result in increased accumulation of callose (beta-1,3-glucan) at the PD, a decrease in PD aperture, defects in root development, and reduced intercellular trafficking. Enhancement of CALS3 expression during phloem development suppressed loss-of-function mutations in the phloem abundant callose synthase, CALS7 indicating that CALS3 is a bona fide callose synthase. CALS3 alleles allowed us to spatially and temporally control the PD aperture between plant tissues. Using this tool, we are able to show that movement of the transcription factor SHORT-ROOT and microRNA1 65 between the stele and the endodermis is PD dependent. Taken together, we conclude that regulated callose biosynthesis at PD is essential for cell signaling.

1 - 22 of 22
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