Journal
DEVELOPMENT
Volume 138, Issue 20, Pages 4465-4473Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.065359
Keywords
Islet1; beta-catenin; Mouse limb initiation; Fgf10
Categories
Funding
- Minnesota Medical Foundation [3962-9211-09]
- American Cancer Society [IRG-58-001-52-IRG04]
- NINDS [5R37NS037116]
- HHMI
- National Institutes of Health [R01 NS049357]
- CIBER
- MICINN
- Fundacion Cellex
- G. Harold and Leila Y. Mathers Charitable Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- Sanofi-Aventis
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The transcriptional basis of vertebrate limb initiation, which is a well-studied system for the initiation of organogenesis, remains elusive. Specifically, involvement of the beta-catenin pathway in limb initiation, as well as its role in hindlimb-specific transcriptional regulation, are under debate. Here, we show that the beta-catenin pathway is active in the limb-forming area in mouse embryos. Furthermore, conditional inactivation of beta-catenin as well as Islet1, a hindlimb-specific factor, in the lateral plate mesoderm results in a failure to induce hindlimb outgrowth. We further show that Islet1 is required for the nuclear accumulation of. catenin and hence for activation of the beta-catenin pathway, and that the beta-catenin pathway maintains Islet1 expression. These two factors influence each other and function upstream of active proliferation of hindlimb progenitors in the lateral plate mesoderm and the expression of a common factor, Fgf10. Our data demonstrate that Islet1 and beta-catenin regulate outgrowth and Fgf10-Fgf8 feedback loop formation during vertebrate hindlimb initiation. Our study identifies Islet1 as a hindlimb-specific transcriptional regulator of initiation, and clarifies the controversy regarding the requirement of beta-catenin for limb initiation.
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