Format

Send to:

Choose Destination
See comment in PubMed Commons below
Hum Mol Genet. 2012 Apr 15;21(8):1888-96. doi: 10.1093/hmg/dds002. Epub 2012 Jan 10.

Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice.

Author information

  • 1Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

Abstract

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 (glioma-associated oncogene homolog)-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.

PMID:
22234993
[PubMed - indexed for MEDLINE]
PMCID:
PMC3313802
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk