干旱区生态环境知识资源中心

Holoprosencephaly is a complex congenital malformation of the brain and is often associated with a spectrum of facial anomalies ranging from normocephaly or nondiagnostic changes to cleft lip/palate (premaxillary dysgenesis), cebocephaly, ethmocephaly, and cyclopia. The primary insult is thought to occur during gastrulation, when prechordal mesenchyme and overlying anterior neural plate undergo complex developmental interactions. Exposure to cyclopamine, a steroid isolated from the desert plant Veratrum californicum, causes holoprosencephaly in mammalian embryos. We have begun to study the pathogenesis of cyclopamine-induced holoprosencephaly and associated craniofacial anomalies in Syrian golden hamsters (Mesocricetus auratus). Embryos were exposed to a single maternal dose of cyclopamine during gastrulation on embryonic day (E) 7.0. By E13.0, 62% of fetuses showed craniofacial malformations, in eluding premaxillary dysgenesis, ocular hypotelorism, and cebocephaly. Facial anomalies were associated with absence of the premaxilla and abnormalities of the midline cranial base, particularly the ethmoid and sphenoid bones. Histological sections from cyclopamine treated embryos at earlier stages showed marked deficiency of cranial mesenchyme derived from the rostral neural crest. Expression of two transcription factors, HNF-3 beta and Hox-b5, which have been implicated in specification of rostral and caudal neural crest cells, respectively were examined immunohistochemically. Treatment with cyclopamine caused a transient loss of HNF-3 beta immunoreactivity in prechordal mesenchyme, but had no effect on Hox-b5 expression. The findings suggest th;at an early event in the pathogenesis of cyclopamine-induced holoprosencephaly may be altered expression of selected proteins in the prechordal mesenchyme and floor plate with secondary impaired development of the adjacent neural plate and cranial neural crest.