title: GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis.
abstract: Inactivation of Gli3, a key component of Hedgehog signaling in vertebrates, results in formation of additional digits (polydactyly) during limb bud development. The analysis of mouse embryos constitutively lacking Gli3 has revealed the essential GLI3 functions in specifying the anteroposterior (AP) limb axis and digit identities. We conditionally inactivated Gli3 during mouse hand plate development, which uncoupled the resulting preaxial polydactyly from known GLI3 functions in establishing AP and digit identities. Our analysis revealed that GLI3 directly restricts the expression of regulators of the G(1)-S cell-cycle transition such as Cdk6 and constrains S phase entry of digit progenitors in the anterior hand plate. Furthermore, GLI3 promotes the exit of proliferating progenitors toward BMP-dependent chondrogenic differentiation by spatiotemporally restricting and terminating the expression of the BMP antagonist Gremlin1. Thus, Gli3 is a negative regulator of the proliferative expansion of digit progenitors and acts as a gatekeeper for the exit to chondrogenic differentiation.
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Javier
authors.initials: J
authors.lastname: Lopez-Rios
authors.forename: Dario
authors.initials: D
authors.lastname: Speziale
authors.forename: Dimitri
authors.initials: D
authors.lastname: Robay
authors.forename: Martina
authors.initials: M
authors.lastname: Scotti
authors.forename: Marco
authors.initials: M
authors.lastname: Osterwalder
authors.forename: Gretel
authors.initials: G
authors.lastname: Nusspaumer
authors.forename: Antonella
authors.initials: A
authors.lastname: Galli
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
authors.forename: Marie
authors.initials: M
authors.lastname: Kmita
authors.forename: Rolf
authors.initials: R
authors.lastname: Zeller
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D020219:Chondrogenesis / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006226:Hand Deformities / Q000209:etiology; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D018878:Limb Buds / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D017689:Polydactyly / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016196:S Phase / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D000074290:Zinc Finger Protein Gli3
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000074290:Zinc Finger Protein Gli3