The Experts below are selected from a list of 8832 Experts worldwide ranked by ideXlab platform
Søren T. Christensen - One of the best experts on this subject based on the ideXlab platform.
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Coordination of TGFβ/BMP signaling is associated with the Primary Cilium
Cilia, 2015Co-Authors: Louise Lindbæk, Karen Koefoed, Lotte B Pedersen, C. B. Warzecha, Johanne B. Mogensen, F Schmid, Lars Allan Larsen, Søren T. ChristensenAbstract:We previously showed that canonical TGFβ signaling is regulated in part by the Primary Cilium, and that ciliary TGFβ signaling is upregulated in stem cells differentiating into cardiomyocytes [1]. Ciliary signaling was shown to be associated with clathrin-dependent endocytosis at the ciliary pocket for activation of SMAD2/3 transcription factors that associate with and promote SMAD4 translocation to the nucleus for target gene expression. Here we investigated whether other receptor types of the TGFβ/BMP superfamily are associated with the Primary Cilium and whether ciliary TGFβ/BMP signaling regulates the commitment of stem cells to different lineages. Using retinal pigment epithelium cells, we demonstrate that multiple receptor systems within the TGFβ/BMP superfamily localize to the Cilium and the ciliary pocket region, including TGFβ receptors I and II (TGF-RI/II), BMP receptors I and II (BMP-RI/II) as well as two isoforms of Activin II receptors (AcRIIa/b) that can be activated by their corresponding ligands to phosphorylate SMAD2/3, SMAD1/5, ERK1/2, AKT and TAK1 at the ciliary base. Further, knockdown of the feedback inhibitor of SMAD signaling, SMURF1, leads to increased SMAD1/5 phosphorylation at the ciliary base, indicating a major role of the Primary Cilium in balancing the cellular level of TGFβ/BMP signaling to control cellular processes during development and in tissue homeostasis. Indeed, the level of ciliary TGFβ/BMP signaling was shown to be associated with the ability to commit stem cells to either neurogenesis or cardiomyogenesis, such that downregulation of ciliary signaling promotes neurogenesis and inhibits cardiomyogenesis. Current studies focus on the mechanisms for targeting of TGFβ/BMP superfamily receptors to the Primary Cilium, trafficking and activation of the receptors within the ciliary compartment, and how these processes contribute to differential cross-talking with other signaling pathways in the Cilium and at the pocket region to control cellular processes during development.
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TGFβ1 Signalling in human mesenchymal stem cells is regulated by the Primary Cilium
Cilia, 2015Co-Authors: Marie-noëlle Labour, Søren T. Christensen, David A. HoeyAbstract:Objective Mesenchymal Stem Cells (MSCs) are mobilized in response to injury to initiate healing and remodelling. TGFb1 is known to induce MSC migration and homing in various tissues including bone. However, the molecular mechanisms involved are poorly understood. TGFb1 signalling has recently been linked to the Primary Cilium in fibroblasts. This cellular microdomain, enriched in transmembrane receptors, could be a specialized centre for TGFb signalling. Therefore, the aim of this study is to investigate the role of the Primary Cilium in TGFb1induced MSC migration.
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The Primary Cilium at a glance.
Journal of Cell Science, 2010Co-Authors: Peter Satir, Lotte B Pedersen, Søren T. ChristensenAbstract:The Primary Cilium, which was first so named by Sergei Sorokin ([Sorokin, 1968][1]), is a solitary organelle that emanates from the cell surface of most mammalian cell types during growth arrest. Increasing evidence suggests that Primary cilia are key coordinators of signaling pathways during
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the Primary Cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation
Journal of Cell Science, 2009Co-Authors: Christian Clement, Gregory J Pazour, Bradley K. Yoder, Lars Allan Larsen, Stine Gry Kristensen, Kjeld Mollgard, Søren T. ChristensenAbstract:Defects in the assembly or function of Primary cilia, which are sensory organelles, are tightly coupled to developmental defects and diseases in mammals. Here, we investigated the function of the Primary Cilium in regulating hedgehog signaling and early cardiogenesis. We report that the pluripotent P19.CL6 mouse stem cell line, which can differentiate into beating cardiomyocytes, forms Primary cilia that contain essential components of the hedgehog pathway, including Smoothened, Patched-1 and Gli2. Knockdown of the Primary Cilium by Ift88 and Ift20 siRNA or treatment with cyclopamine, an inhibitor of Smoothened, blocks hedgehog signaling in P19.CL6 cells, as well as differentiation of the cells into beating cardiomyocytes. E11.5 embryos of the Ift88tm1Rpw (Ift88-null) mice, which form no cilia, have ventricular dilation, decreased myocardial trabeculation and abnormal outflow tract development. These data support the conclusion that cardiac Primary cilia are crucial in early heart development, where they partly coordinate hedgehog signaling.
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The Primary Cilium is a sensory organelle that regulates growth control and tissue homeostasis
The FASEB Journal, 2006Co-Authors: Søren T. Christensen, Gregory J Pazour, Christian Clement, Linda Schneider, Else K Hoffmann, Peter SatirAbstract:The growth-arrest specific receptor tyrosine kinase, PDGFRa, is up-regulated and targeted to the Primary Cilium during growth arrest in NIH3T3 cells and Primary cultures of mouse embryonic fibrobla...
Richard Bayliss - One of the best experts on this subject based on the ideXlab platform.
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The Primary Cilium: guardian of organ development and homeostasis.
Organogenesis, 2014Co-Authors: Andrew M. Fry, Michelle J Leaper, Richard BaylissAbstract:The Primary Cilium is an antenna-like organelle that plays a vital role in organ generation and maintenance. It protrudes from the cell surface where it receives signals from the surrounding environment and relays them into the cell. These signals are then integrated to give the required outputs in terms of proliferation, differentiation, migration and polarization that ultimately lead to organ development and homeostasis. Defects in cilia function underlie a wide range of diverse but related human developmental or degenerative diseases. Collectively known as ciliopathies, these disorders present with varying severity and multiple organ involvement. The appreciation of the medical importance of the Primary Cilium has stimulated a huge effort into studies of the underlying cellular mechanisms. These in turn have revealed that ciliopathies result not only from defective assembly or organization of the Primary Cilium, but also from impaired ciliary signaling. This special edition of Organogenesis contains a ...
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The Primary Cilium: guardian of organ development and homeostasis.
Organogenesis, 2014Co-Authors: Andrew M. Fry, Michelle J Leaper, Richard BaylissAbstract:The Primary Cilium is an antenna-like organelle that plays a vital role in organ generation and maintenance. It protrudes from the cell surface where it receives signals from the surrounding environment and relays them into the cell. These signals are then integrated to give the required outputs in terms of proliferation, differentiation, migration and polarization that ultimately lead to organ development and homeostasis. Defects in cilia function underlie a wide range of diverse but related human developmental or degenerative diseases. Collectively known as ciliopathies, these disorders present with varying severity and multiple organ involvement. The appreciation of the medical importance of the Primary Cilium has stimulated a huge effort into studies of the underlying cellular mechanisms. These in turn have revealed that ciliopathies result not only from defective assembly or organization of the Primary Cilium, but also from impaired ciliary signaling. This special edition of Organogenesis contains a set of review articles that highlight the role of the Primary Cilium in organ development and homeostasis, much of which has been learnt from studies of the associated human diseases. Here, we provide an introductory overview of our current understanding of the structure and function of the Cilium, with a focus on the signaling pathways that are coordinated by Primary cilia to ensure proper organ generation and maintenance.
Gregory J Pazour - One of the best experts on this subject based on the ideXlab platform.
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the Primary Cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation
Journal of Cell Science, 2009Co-Authors: Christian Clement, Gregory J Pazour, Bradley K. Yoder, Lars Allan Larsen, Stine Gry Kristensen, Kjeld Mollgard, Søren T. ChristensenAbstract:Defects in the assembly or function of Primary cilia, which are sensory organelles, are tightly coupled to developmental defects and diseases in mammals. Here, we investigated the function of the Primary Cilium in regulating hedgehog signaling and early cardiogenesis. We report that the pluripotent P19.CL6 mouse stem cell line, which can differentiate into beating cardiomyocytes, forms Primary cilia that contain essential components of the hedgehog pathway, including Smoothened, Patched-1 and Gli2. Knockdown of the Primary Cilium by Ift88 and Ift20 siRNA or treatment with cyclopamine, an inhibitor of Smoothened, blocks hedgehog signaling in P19.CL6 cells, as well as differentiation of the cells into beating cardiomyocytes. E11.5 embryos of the Ift88tm1Rpw (Ift88-null) mice, which form no cilia, have ventricular dilation, decreased myocardial trabeculation and abnormal outflow tract development. These data support the conclusion that cardiac Primary cilia are crucial in early heart development, where they partly coordinate hedgehog signaling.
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The Primary Cilium is a sensory organelle that regulates growth control and tissue homeostasis
The FASEB Journal, 2006Co-Authors: Søren T. Christensen, Gregory J Pazour, Christian Clement, Linda Schneider, Else K Hoffmann, Peter SatirAbstract:The growth-arrest specific receptor tyrosine kinase, PDGFRa, is up-regulated and targeted to the Primary Cilium during growth arrest in NIH3T3 cells and Primary cultures of mouse embryonic fibrobla...
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pdgfrαα signaling is regulated through the Primary Cilium in fibroblasts
Current Biology, 2005Co-Authors: Linda Schneider, Gregory J Pazour, Peter Satir, Christian Clement, Else K Hoffmann, Stefan C Teilmann, Søren T. ChristensenAbstract:Recent findings show that cilia are sensory organelles that display specific receptors and ion channels, which transmit signals from the extracellular environment via the Cilium to the cell to control tissue homeostasis and function. Agenesis of Primary cilia or mislocation of ciliary signal components affects human pathologies, such as polycystic kidney disease and disorders associated with Bardet-Biedl syndrome. Primary cilia are essential for hedgehog ligand-induced signaling cascade regulating growth and patterning. Here, we show that the Primary Cilium in fibroblasts plays a critical role in growth control via platelet-derived growth factor receptor alpha (PDGFRalpha), which localizes to the Primary Cilium during growth arrest in NIH3T3 cells and Primary cultures of mouse embryonic fibroblasts. Ligand-dependent activation of PDGFRalphaalpha is followed by activation of Akt and the Mek1/2-Erk1/2 pathways, with Mek1/2 being phosphorylated within the Cilium and at the basal body. Fibroblasts derived from Tg737(orpk) mutants fail to form normal cilia and to upregulate the level of PDGFRalpha; PDGF-AA fails to activate PDGFRalphaalpha and the Mek1/2-Erk1/2 pathway. Signaling through PDGFRbeta, which localizes to the plasma membrane, is maintained at comparable levels in wild-type and mutant cells. We propose that ciliary PDGFRalphaalpha signaling is linked to tissue homeostasis and to mitogenic signaling pathways.
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The vertebrate Primary Cilium is a sensory organelle
Current Opinion in Cell Biology, 2003Co-Authors: Gregory J Pazour, George B. WitmanAbstract:Abstract The Primary Cilium is a generally non-motile Cilium that occurs singly on most cells in the vertebrate body. The function of this organelle, which has been the subject of much speculation but little experimentation, has been unknown. Recent findings reveal that the Primary Cilium is an antenna displaying specific receptors and relaying signals from these receptors to the cell body. For example, kidney Primary cilia display polycystin-2, which forms part of a Ca 2+ channel that initiates a signal that controls cell differentiation and proliferation. Kidney Primary cilia also are mechanosensors that, when bent, initiate a Ca 2+ signal that spreads throughout the cell and to neighboring cells. Primary cilia on other cell types specifically display different receptors, including those for somatostatin and serotonin.
Andrew M. Fry - One of the best experts on this subject based on the ideXlab platform.
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The Primary Cilium: guardian of organ development and homeostasis.
Organogenesis, 2014Co-Authors: Andrew M. Fry, Michelle J Leaper, Richard BaylissAbstract:The Primary Cilium is an antenna-like organelle that plays a vital role in organ generation and maintenance. It protrudes from the cell surface where it receives signals from the surrounding environment and relays them into the cell. These signals are then integrated to give the required outputs in terms of proliferation, differentiation, migration and polarization that ultimately lead to organ development and homeostasis. Defects in cilia function underlie a wide range of diverse but related human developmental or degenerative diseases. Collectively known as ciliopathies, these disorders present with varying severity and multiple organ involvement. The appreciation of the medical importance of the Primary Cilium has stimulated a huge effort into studies of the underlying cellular mechanisms. These in turn have revealed that ciliopathies result not only from defective assembly or organization of the Primary Cilium, but also from impaired ciliary signaling. This special edition of Organogenesis contains a ...
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The Primary Cilium: guardian of organ development and homeostasis.
Organogenesis, 2014Co-Authors: Andrew M. Fry, Michelle J Leaper, Richard BaylissAbstract:The Primary Cilium is an antenna-like organelle that plays a vital role in organ generation and maintenance. It protrudes from the cell surface where it receives signals from the surrounding environment and relays them into the cell. These signals are then integrated to give the required outputs in terms of proliferation, differentiation, migration and polarization that ultimately lead to organ development and homeostasis. Defects in cilia function underlie a wide range of diverse but related human developmental or degenerative diseases. Collectively known as ciliopathies, these disorders present with varying severity and multiple organ involvement. The appreciation of the medical importance of the Primary Cilium has stimulated a huge effort into studies of the underlying cellular mechanisms. These in turn have revealed that ciliopathies result not only from defective assembly or organization of the Primary Cilium, but also from impaired ciliary signaling. This special edition of Organogenesis contains a set of review articles that highlight the role of the Primary Cilium in organ development and homeostasis, much of which has been learnt from studies of the associated human diseases. Here, we provide an introductory overview of our current understanding of the structure and function of the Cilium, with a focus on the signaling pathways that are coordinated by Primary cilia to ensure proper organ generation and maintenance.
Peter Satir - One of the best experts on this subject based on the ideXlab platform.
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The Primary Cilium at a glance.
Journal of Cell Science, 2010Co-Authors: Peter Satir, Lotte B Pedersen, Søren T. ChristensenAbstract:The Primary Cilium, which was first so named by Sergei Sorokin ([Sorokin, 1968][1]), is a solitary organelle that emanates from the cell surface of most mammalian cell types during growth arrest. Increasing evidence suggests that Primary cilia are key coordinators of signaling pathways during
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The Primary Cilium is a sensory organelle that regulates growth control and tissue homeostasis
The FASEB Journal, 2006Co-Authors: Søren T. Christensen, Gregory J Pazour, Christian Clement, Linda Schneider, Else K Hoffmann, Peter SatirAbstract:The growth-arrest specific receptor tyrosine kinase, PDGFRa, is up-regulated and targeted to the Primary Cilium during growth arrest in NIH3T3 cells and Primary cultures of mouse embryonic fibrobla...
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pdgfrαα signaling is regulated through the Primary Cilium in fibroblasts
Current Biology, 2005Co-Authors: Linda Schneider, Gregory J Pazour, Peter Satir, Christian Clement, Else K Hoffmann, Stefan C Teilmann, Søren T. ChristensenAbstract:Recent findings show that cilia are sensory organelles that display specific receptors and ion channels, which transmit signals from the extracellular environment via the Cilium to the cell to control tissue homeostasis and function. Agenesis of Primary cilia or mislocation of ciliary signal components affects human pathologies, such as polycystic kidney disease and disorders associated with Bardet-Biedl syndrome. Primary cilia are essential for hedgehog ligand-induced signaling cascade regulating growth and patterning. Here, we show that the Primary Cilium in fibroblasts plays a critical role in growth control via platelet-derived growth factor receptor alpha (PDGFRalpha), which localizes to the Primary Cilium during growth arrest in NIH3T3 cells and Primary cultures of mouse embryonic fibroblasts. Ligand-dependent activation of PDGFRalphaalpha is followed by activation of Akt and the Mek1/2-Erk1/2 pathways, with Mek1/2 being phosphorylated within the Cilium and at the basal body. Fibroblasts derived from Tg737(orpk) mutants fail to form normal cilia and to upregulate the level of PDGFRalpha; PDGF-AA fails to activate PDGFRalphaalpha and the Mek1/2-Erk1/2 pathway. Signaling through PDGFRbeta, which localizes to the plasma membrane, is maintained at comparable levels in wild-type and mutant cells. We propose that ciliary PDGFRalphaalpha signaling is linked to tissue homeostasis and to mitogenic signaling pathways.