title: A switch from low to high Shh activity regulates establishment of limb progenitors and signaling centers.
abstract: The patterning and growth of the embryonic vertebrate limb is dependent on Sonic hedgehog (Shh), a morphogen that regulates the activity of Gli transcription factors. However, Shh expression is not observed during the first 12 hr of limb development. During this phase, the limb bud is prepatterned into anterior and posterior regions through the antagonistic actions of transcription factors Gli3 and Hand2. We demonstrate that precocious activation of Shh signaling during this early phase interferes with the Gli3-dependent specification of anterior progenitors, disturbing establishment of signaling centers and normal outgrowth of the limb. Our findings illustrate that limb development requires a sweet spot in the level and timing of pathway activation that allows for the Shh-dependent expansion of posterior progenitors without interfering with early prepatterning functions of Gli3/Gli3R or specification of anterior progenitors.
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Olena
authors.initials: O
authors.lastname: Zhulyn
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Danyi
authors.initials: D
authors.lastname: Li
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Deimling
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Niki Alizadeh
authors.initials: NA
authors.lastname: Vakili
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Rong
authors.initials: R
authors.lastname: Mo
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
authors.forename: Miao-Hsueh
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
authors.forename: Pao-Tien
authors.initials: PT
authors.lastname: Chuang
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Sevan
authors.initials: S
authors.lastname: Hopyan
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: cchui@sickkids.ca.
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019521:Body Patterning / Q000502:physiology; D002417:Cattle; D002645:Chickens; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D018878:Limb Buds / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D016547:Kinesins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000074290:Zinc Finger Protein Gli3; C465571:Gli3 protein, mouse; C498766:Hand2 protein, mouse; C465570:Shh protein, mouse; C490763:Sufu protein, mouse; C543639:Kif7 protein, mouse