Human Molecular Genetics, 2000, Vol. 9, No. 10 1473-1480
© 2000 Oxford University Press
Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome
School of Biological Sciences and Department of Dental Medicine and Surgery, 3.239 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK and 1Department of Experimental Pathology, Lund University Hospital, S-22185 Lund, Sweden
Treacher Collins syndrome (TCS) is an autosomal dominant disorder of human craniofacial development that results from loss-of-function mutations in the gene TCOF1. Although this gene has been demonstrated to encode the nucleolar phosphoprotein treacle, the developmental mechanism underlying TCS remains elusive, particularly as expression studies have shown that the murine orthologue, Tcof1, is widely expressed. To investigate the molecular pathogenesis of TCS, we replaced exon 1 of Tcof1 with a neomycin-resistance cassette via homologous recombination in embryonic stem cells. Tcof1 heterozygous mice die perinatally as a result of severe craniofacial anomalies that include agenesis of the nasal passages, abnormal development of the maxilla, exencephaly and anophthalmia. These defects arise due to a massive increase in the levels of apoptosis in the prefusion neural folds, which are the site of the highest levels of Tcof1 expression. Our results demonstrate that TCS arises from haploinsufficiency of a protein that plays a crucial role in craniofacial development and indicate that correct dosage of treacle is essential for survival of cephalic neural crest cells.
+ To whom correspondence should be addressed. Tel: +44 161 275 5620; Fax: +44 161 275 5620; Email: mike.dixon@man.ac.uk
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