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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4465-4473
Number of pages9
JournalDevelopment
Volume138
Issue number20
DOIs
StatePublished - Oct 15 2011

Keywords

  • Fgf10
  • Islet1
  • Mouse limb initiation
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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