Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch D H, McMahon A P, Sommer L, Boussadia O, Kemler R
Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany.
Development. 2001 Apr;128(8):1253-64. doi: 10.1242/dev.128.8.1253.
beta-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of beta-catenin during brain morphogenesis, by specifically inactivating the beta-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of beta-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. beta-Catenin gene deletion resulted in dramatic brain malformation and failure of craniofacial development. Absence of part of the midbrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(-/-)), suggesting that Wnt1 acts through beta-catenin in controlling midbrain-hindbrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for beta-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (beta-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of beta-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during brain and craniofacial development.
β-连环蛋白是钙黏蛋白-连环蛋白细胞黏附复合体和Wnt信号通路的核心组成部分。我们通过特异性地使Wnt1表达区域中的β-连环蛋白基因失活，研究了β-连环蛋白在脑形态发生过程中的作用。为实现这一点，将带有条件性（“floxed”）等位基因的β-连环蛋白（其所需外显子两侧为loxP重组序列）的小鼠与在Wnt1调控序列控制下表达Cre重组酶的转基因小鼠进行杂交。β-连环蛋白基因缺失导致严重的脑畸形和颅面发育失败。中脑部分和整个小脑的缺失让人联想到传统的Wnt1基因敲除小鼠（Wnt1(-/-)），这表明Wnt1通过β-连环蛋白控制中脑-后脑发育。在缺乏Wnt1的胚胎中未观察到的颅面表型，表明β-连环蛋白在神经嵴细胞命运中发挥作用。对神经管外植体的分析表明，β-连环蛋白在迁移的神经嵴细胞前体中被有效删除。这一点，连同迁移至颅神经节和软骨前凝聚区域的细胞中凋亡增加，表明β-连环蛋白的缺失影响神经嵴细胞的存活和/或分化。我们的结果证明了β-连环蛋白在脑和颅面发育的形态发生过程中的关键作用。
