Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development

beta -Catenin is a central component of both the cadherin-catenin cell adhe sion complex and the Wnt signaling pathway. We have investigated the role o f beta -catenin during brain morphogenesis, by specifically inactivating th e beta -catenin gene in the region of Wnt1 expression. To achieve this, mic e with a conditional ('floxed') allele of beta -catenin with required exons banked by loxP recombination sequences were intercrossed with transgenic m ice that expressed Cre recombinase under control of Wnt1 regulatory sequenc es. beta -catenin gene deletion resulted in dramatic brain malformation and failure of craniofacial development. Absence of part of the midbrain and a ll of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1 (-/-)), suggesting that Wnt1 acts through beta -catenin in controlling midb rain-hindbrain development. The craniofacial phenotype, not observed in emb ryos that lack Wnt1, indicates a role for beta -catenin in the fate of neur al crest cells. Analysis of neural tube explants shows that beta -catenin i s efficiently deleted in migrating neural crest cell precursors. This, toge ther with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of bet a -catenin affects neural crest cell survival and/or differentiation. Our r esults demonstrate the pivotal role of beta -catenin in morphogenetic proce sses during brain and craniofacial development.