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Islet1-mediated activation of the β-catenin pathway is necessary for hindlimb initiation in mice

Research output: Contribution to journalArticle

Yasuhiko Kawakami, Merce Marti, Hiroko Kawakami, Junji Itou, Thu Quach, Austin Johnson, Setsuko Sahara, Dennis D. M. O'Leary, Yasushi Nakagawa, Mark Lewandoski, Samuel Pfaff, Sylvia M. Evans, Juan Carlos Izpisua Belmonte

Original languageEnglish
Pages (from-to)4465-4473
Number of pages9
JournalDevelopment (Cambridge): for advances in developmental biology and stem cells
Volume138
Issue number20
DOIs
Publication statusPublished - 15 Oct 2011

King's Authors

Abstract

The transcriptional basis of vertebrate limb initiation, which is a well-studied system for the initiation of organogenesis, remains elusive. Specifically, involvement of the β-catenin pathway in limb initiation, as well as its role in hindlimb-specific transcriptional regulation, are under debate. Here, we show that the β-catenin pathway is active in the limb-forming area in mouse embryos. Furthermore, conditional inactivation of β-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 β-catenin and hence for activation of the β-catenin pathway, and that the β-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 β-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 β-catenin for limb initiation.

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