title: Islet1-mediated activation of the β-catenin pathway is necessary for hindlimb initiation in mice.
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.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA. kawak005@umn.edu
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Merce
authors.initials: M
authors.lastname: Marti
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawakami
authors.forename: Junji
authors.initials: J
authors.lastname: Itou
authors.forename: Thu
authors.initials: T
authors.lastname: Quach
authors.forename: Austin
authors.initials: A
authors.lastname: Johnson
authors.forename: Setsuko
authors.initials: S
authors.lastname: Sahara
authors.forename: Dennis D M
authors.initials: DD
authors.lastname: O'Leary
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
authors.forename: Samuel
authors.initials: S
authors.lastname: Pfaff
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000196:embryology* / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C496464:Fgf10 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051176:beta Catenin; C063843:insulin gene enhancer binding protein Isl-1; D051524:Fibroblast Growth Factor 8