Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1.
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 a...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3636256?pdf=render |
| _version_ | 1830428648793964544 |
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| author | Henner F Farin Timo H-W Lüdtke Martina K Schmidt Susann Placzko Karin Schuster-Gossler Marianne Petry Vincent M Christoffels Andreas Kispert |
| author_facet | Henner F Farin Timo H-W Lüdtke Martina K Schmidt Susann Placzko Karin Schuster-Gossler Marianne Petry Vincent M Christoffels Andreas Kispert |
| author_sort | Henner F Farin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T01:23:20Z |
| format | Article |
| id | doaj.art-a15249ecec5e4ede80a199ea50d7dc18 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T01:23:20Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-a15249ecec5e4ede80a199ea50d7dc182022-12-21T19:20:36ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0194e100346710.1371/journal.pgen.1003467Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1.Henner F FarinTimo H-W LüdtkeMartina K SchmidtSusann PlaczkoKarin Schuster-GosslerMarianne PetryVincent M ChristoffelsAndreas KispertVertebrate 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.http://europepmc.org/articles/PMC3636256?pdf=render |
| spellingShingle | Henner F Farin Timo H-W Lüdtke Martina K Schmidt Susann Placzko Karin Schuster-Gossler Marianne Petry Vincent M Christoffels Andreas Kispert Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. PLoS Genetics |
| title | Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. |
| title_full | Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. |
| title_fullStr | Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. |
| title_full_unstemmed | Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. |
| title_short | Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. |
| title_sort | tbx2 terminates shh fgf signaling in the developing mouse limb bud by direct repression of gremlin1 |
| url | http://europepmc.org/articles/PMC3636256?pdf=render |
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