Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of human craniofacial development that results from loss-of-function mutations in th e gene TCOF1. Although this gene has been demonstrated to encode the nucleo lar phosphoprotein treacle, the developmental mechanism underlying TCS rema ins elusive, particularly as expression studies have shown that the murine orthologue, Tcof1, is widely expressed. To investigate the molecular pathog enesis of TCS, we replaced exon 1 of Tcof1 with a neomycin-resistance casse tte via homologous recombination in embryonic stem cells. Tcof1 heterozygou s mice die perinatally as a result of severe craniofacial anomalies that in clude 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 si te of the highest levels of Tcof1 expression. Our results demonstrate that TCS arises from haploinsufficiency of a protein that plays a crucial role i n craniofacial development and indicate that correct dosage of treacle is e ssential for survival of cephalic neural crest cells.