Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1
| Autor: | Marianne Petry, Andreas Kispert, Timo H. Lüdtke, Henner F. Farin, Vincent M. Christoffels, Susann Placzko, Karin Schuster-Gossler, Martina K. Schmidt |
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| Přispěvatelé: | ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Medical Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Apical ectodermal ridge
Cancer Research Anatomy and Physiology Limb Development Fibroblast growth factor Epithelium Mesoderm Mice 0302 clinical medicine Morphogenesis Pattern Formation Sonic hedgehog Musculoskeletal System Musculoskeletal Anatomy Genetics (clinical) 0303 health sciences Gene Expression Regulation Developmental Cell Differentiation Cell biology Phenotype medicine.anatomical_structure Bone Morphogenetic Proteins embryonic structures Cytokines Intercellular Signaling Peptides and Proteins Signal Transduction Research Article medicine.medical_specialty animal structures Limb Buds lcsh:QH426-470 DNA transcription Biology Bone morphogenetic protein Molecular Genetics 03 medical and health sciences Limb bud Internal medicine Genetics medicine Animals Limb development Hedgehog Proteins Gene Regulation Birth Defects Bone Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Molecular Development Fibroblast Growth Factors lcsh:Genetics Cartilage Endocrinology Zone of polarizing activity biology.protein Gene expression T-Box Domain Proteins 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 9, Iss 4, p e1003467 (2013) PLoS Genetics PLoS genetics, 9(4). Public Library of Science PLoS Genetics; Vol 9 |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction. Author Summary Developmental defects of the limb skeleton, such as variations from the normal number of digits, can result from an abnormal size of the early limb bud. The mechanisms that restrict limb bud growth to avoid polydactyly, i.e. the formation of extra digits, are unclear. Gremlin 1 (Grem1) has been identified as a key regulator in this process via its role as secreted antagonist of Bone morphogenetic protein (Bmp) signaling. But it remains unknown how Grem1 expression is switched off appropriately to achieve normal limb bud size. Here we show in the mouse embryo that T-box transcription factor 2 (Tbx2) directly represses Grem1. We show that Tbx2-positive mesenchymal cells at the posterior margin of the limb bud create a Grem1-negative zone that expands concomitantly with limb bud growth. Progressive displacement of the source of Grem1 and its target region, the apical ectodermal ridge, eventually disrupts epithelial-mesenchymal signaling that is crucial for further proliferative expansion. Our data show how local control of signaling activities is translated into the architecture of the adult skeleton, i.e. the number or digits, which helps us to understand the molecular bases of human polydactyly. |
| Databáze: | OpenAIRE |
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