Embryology Unit, Children's Medical Research Institute, University of Sydney, 214 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia.
Development. 2011 Feb;138(4):667-76. doi: 10.1242/dev.052803. Epub 2011 Jan 12.
In mouse embryos, loss of Dickkopf-1 (DKK1) activity is associated with an ectopic activation of WNT signalling responses in the precursors of the craniofacial structures and leads to a complete truncation of the head at early organogenesis. Here, we show that ENU-induced mutations of genes coding for two WNT canonical pathway factors, the co-receptor LRP6 and the transcriptional co-activator β-catenin, also elicit an ectopic signalling response and result in loss of the rostral tissues of the forebrain. Compound mutant embryos harbouring combinations of mutant alleles of Lrp6, Ctnnb1 and Dkk1 recapitulate the partial to complete head truncation phenotype of individual homozygous mutants. The demonstration of a synergistic interaction of Dkk1, Lrp6 and Ctnnb1 provides compelling evidence supporting the concepts that (1) stringent regulation of the level of canonical WNT signalling is necessary for head formation, (2) activity of the canonical pathway is sufficient to account for the phenotypic effects of mutations in three different components of the signal cascade and (3) rostral parts of the brain and the head are differentially more sensitive to canonical WNT signalling and their development is contingent on negative modulation of WNT signalling activity.
在小鼠胚胎中，Dickkopf-1（DKK1）活性的丧失与颅面结构前体细胞中 WNT 信号反应的异位激活有关，并导致早期器官发生时头部完全截断。在这里，我们表明，ENU 诱导的编码两个 WNT 经典途径因子的基因的突变，即共受体 LRP6 和转录共激活子β-catenin，也引发了异位信号反应，并导致前脑的颅组织缺失。携带 Lrp6、Ctnnb1 和 Dkk1 突变等位基因组合的复合突变体胚胎重现了单个纯合突变体的部分至完全头部截断表型。Dkk1、Lrp6 和 Ctnnb1 的协同相互作用的证明提供了令人信服的证据，支持以下概念：（1）严格调节经典 WNT 信号的水平对于头部形成是必要的；（2）经典途径的活性足以解释信号级联的三个不同成分中的突变的表型效应；（3）脑和头部的前部对经典 WNT 信号更敏感，它们的发育取决于 WNT 信号活性的负调节。
