Human Molecular Genetics Advance Access originally published online on May 3, 2007
Human Molecular Genetics 2007 16(12):1423-1436; doi:10.1093/hmg/ddm093
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Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat–Wilson syndrome
1 Laboratory of Molecular Biology (Celgen), Department of Molecular and Developmental Genetics (VIB11), |nFlanders Institute of Biotechnology (VIB) and 2 Department of Human Genetics, KULeuven, Herestraat 49, B-3000 Leuven, Belgium
* To whom correspondence should be addressed at: Laboratory of Molecular Biology (Celgen), KULeuven, VIB Department of Molecular and Developmental Genetics, Flanders Institute of Biotechnology (VIB), Campus Gasthuisberg, Building Ond&Nav1, PO Box 812, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345916; Fax: +32 16345933; Email: tom.vandeputte{at}med.kuleuven.be
Mowat–Wilson syndrome is a recently delineated autosomal dominant developmental anomaly, whereby heterozygous mutations in the ZFHX1B gene cause mental retardation, delayed motor development, epilepsy and a wide spectrum of clinically heterogeneous features, suggestive of neurocristopathies at the cephalic, cardiac and vagal levels. However, our understanding of the etiology of this condition at the cellular level remains vague. This study presents the Zfhx1b protein expression domain in mouse embryos and correlates this with a novel mouse model involving a conditional mutation in the Zfhx1b gene in neural crest precursor cells. These mutant mice display craniofacial and gastrointestinal malformations that show resemblance to those found in human patients with Mowat–Wilson syndrome. In addition to these clinically recognized alterations, we document developmental defects in the heart, melanoblasts and sympathetic and parasympathetic anlagen. The latter observations in our mouse model for Mowat–Wilson suggest a hitherto unknown role for Zfhx1b in the development of these particular neural crest derivatives, which is a set of observations that should be acknowledged in the clinical management of this genetic disorder.
Present address: Galapagos S.A., Generaal De Wittelaan L11, B-2800 Mechelen, Belgium.
Present address: Cell Biology and Histology (CYTO), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Jette, Belgium.
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