| Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice. | |
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MedLine Citation:
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PMID: 22234993 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Limb anomalies are important birth defects that are incompletely understood genetically and mechanistically. GLI3, a mediator of hedgehog signaling, is a genetic cause of limb malformations including pre- and postaxial polydactyly, Pallister-Hall syndrome and Greig cephalopolysyndactyly. A closely related Gli-superfamily member, ZIC3, causes X-linked heterotaxy syndrome in humans but has not been investigated in limb development. During limb development, post-translational processing of Gli3 from activator to repressor antagonizes and posteriorly restricts sonic hedgehog (Shh). We demonstrate that Zic3 and Gli3 expression overlap in developing limbs and that Zic3 converts Gli3 from repressor to activator in vitro. In Gli3 mutant mice, Zic3 loss of function abrogates ectopic Shh expression in anterior limb buds, limits overexpression in the zone of polarizing activity, and normalizes aberrant Gli3 repressor/Gli3 activator ratios observed in Gli3+/- embryos. Zic3 null; Gli3+/- neonates show rescue of the polydactylous phenotype seen in Gli3+/- animals. These studies identify a previously unrecognized role for Zic3 in regulating limb digit number via its modifying effect on Gli3 and Shh expression levels. Together these results indicate that two Gli superfamily members that cause disparate human congenital malformation syndromes interact genetically and demonstrate the importance of Zic3 in regulating Shh pathway in developing limbs. |
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Authors:
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Malgorzata E Quinn; Allison Haaning; Stephanie M Ware |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-10 |
Journal Detail:
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Title: Human molecular genetics Volume: - ISSN: 1460-2083 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Cincinnati Children's Hospital Medical Center, Division of Molecular Cardiovascular Biology and University of Cincinnati College of Medicine. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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