Perinatal Lethality and Multiple Craniofacial Malformations in MSX2 Transgenic Mice

MSX2 is a homeodomain transcription factor that has been implicated in craniofacial morphogenesis on the basis of its expression pattern during mouse development and the finding of a missense mutation (P148H) in humans affected with Boston-type craniosynostosis. We have generated transgenic mice carrying a 34 kb DNA fragment encompassing a human MSX2 gene encoding either wild-type or mutant (P148H) MSX2. Inheritance of either transgene resulted in perinatal lethality and multiple craniofacial malformations of varying severity, including mandibular hypoplasia, cleft secondary palate, exencephaly, and median facial cleft, which are among the severe craniofacial malformations observed in humans. Transgenic mice also manifested aplasia of the interparietal bone and decreased ossification of the hyoid. Transgene-induced malformations involved cranial neural-crest derivatives, were characterized by a deficiency of tissue, and were similar to malformations associated with embryonic exposure to ethanol or retinoic acid, teratogens that cause increased cell death. Together with previous observations implicating MSX2 expression in developmentally-programmed cell death, these results suggest that wild-type levels of MSX2 activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis.