Progression of vertebrate limb development through SHH-mediated counteraction of GLI3.
Distal limb development and specification of digit identities in tetrapods are under the control of a mesenchymal organizer called the polarizing region. Sonic Hedgehog (SHH) is the morphogenetic signal produced by the polarizing region in the posterior limb bud. Ectopic anterior SHH signaling induces digit duplications and has been suspected as a major cause underlying congenital malformations that result in digit polydactyly. Here, we report that the polydactyly of Gli3-deficient mice arises independently of SHH signaling. Disruption of one or both Gli3 alleles in mouse embryos lacking Shh progressively restores limb distal development and digit formation. Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development.
te Welscher
Pascal
P
Department of Developmental Biology, Faculty of Biology, Utrecht University, Padualaan 8, NL-3584 CH Utrecht, Netherlands.
Zuniga
Aimée
A
Kuijper
Sanne
S
Drenth
Thijs
T
Goedemans
Hans J
HJ
Meijlink
Frits
F
Zeller
Rolf
R
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D016923:Cell Death; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005121:Extremities / Q000196:embryology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D018878:Limb Buds / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D017689:Polydactyly / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3; C416676:ALX4 protein, human; C113178:Grem1 protein, mouse; C486399:GREM1 protein, human; C465571:Gli3 protein, mouse; C498766:Hand2 protein, mouse; C465570:Shh protein, mouse; C112971:fibroblast growth factor 14; C410915:hand2 protein, zebrafish