A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning
- PMID: 19229034
- DOI: 10.1126/science.1168755
A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning
Abstract
Embryogenesis depends on self-regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial-mesenchymal (e-m) feedback loops between sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling involving the bone morphogenetic protein (BMP) antagonist Gremlin1 (GREM1). By combining mouse molecular genetics with mathematical modeling, we showed that BMP4 first initiates and SHH then propagates e-m feedback signaling through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/GREM1 module to the slower SHH/GREM1/FGF e-m feedback loop. This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways.
Similar articles
-
The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells.Science. 2004 Jul 16;305(5682):396-9. doi: 10.1126/science.1096966. Science. 2004. PMID: 15256670
-
A BMP-Shh negative-feedback loop restricts Shh expression during limb development.Development. 2009 Nov;136(22):3779-89. doi: 10.1242/dev.036418. Development. 2009. PMID: 19855020
-
Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis.Development. 2004 Jul;131(14):3401-10. doi: 10.1242/dev.01251. Epub 2004 Jun 16. Development. 2004. PMID: 15201225
-
The Apical Ectodermal Ridge: morphological aspects and signaling pathways.Int J Dev Biol. 2008;52(7):857-71. doi: 10.1387/ijdb.072416mf. Int J Dev Biol. 2008. PMID: 18956316 Review.
-
[Signaling molecules involved in induction and early patterning of limb buds].Kaibogaku Zasshi. 1998 Dec;73(6):655-66. Kaibogaku Zasshi. 1998. PMID: 9990203 Review. Japanese.
Cited by
-
Combinatorial regulatory states define cell fate diversity during embryogenesis.Nat Commun. 2024 Aug 9;15(1):6841. doi: 10.1038/s41467-024-50822-y. Nat Commun. 2024. PMID: 39122679 Free PMC article.
-
The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice.Bone Res. 2024 Apr 1;12(1):21. doi: 10.1038/s41413-024-00322-y. Bone Res. 2024. PMID: 38561387 Free PMC article.
-
How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms?Philos Trans R Soc Lond B Biol Sci. 2024 Apr 22;379(1900):20230045. doi: 10.1098/rstb.2023.0045. Epub 2024 Mar 4. Philos Trans R Soc Lond B Biol Sci. 2024. PMID: 38432317 Free PMC article. Review.
-
Association between IRF6, TP63, GREM1 Gene Polymorphisms and Non-Syndromic Orofacial Cleft Phenotypes in Vietnamese Population: A Case-Control and Family-Based Study.Genes (Basel). 2023 Oct 25;14(11):1995. doi: 10.3390/genes14111995. Genes (Basel). 2023. PMID: 38002937 Free PMC article.
-
Developmental regulation of conserved non-coding element evolution provides insights into limb loss in squamates.Sci China Life Sci. 2023 Oct;66(10):2399-2414. doi: 10.1007/s11427-023-2362-5. Epub 2023 May 22. Sci China Life Sci. 2023. PMID: 37256419
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
