Wnt Signaling in Craniofacial Developmental Disorders

描述（由申请人提供）：我们的长期研究目标是揭示Wnt信号突变动物模型颅面出生缺陷的分子和遗传机制，为开发创新的预防和治疗策略提供基础。先天性颅面缺陷，尤其是伴有或不伴有腭裂的唇裂（CLP），是人类最常见的出生缺陷之一。CLP是由于早期胚胎发育过程中唇或上颚的融合失败造成的，其病因复杂，但在很大程度上尚不清楚。典型的Wnt/ss-catenin通路在形态发生中起重要作用，该通路中的基因突变与人类遗传疾病有关。然而，典型的Wnt通路在口腔面部发育中的作用，特别是在唇腭裂的形成和融合过程中，仍然知之甚少。我们最近发现典型的Wnt信号在口面部原基的融合位点被激活，并且在Wnt信号分子单基因突变的小鼠中发生CLP。突变体在面部外胚层和间质中表现出显著的形态发生运动和候选Wnt靶基因改变。因此，我们假设CLP是由唇/腭形成和融合过程中Wnt/ss-catenin信号通路及其下游靶点在面部外胚层/上皮和间质中的破坏引起的。目的1将评估我们的假设，即面部外胚层典型Wnt信号的条件失活将导致CLP。目的2将探讨两个Wnt信号共受体是否在面部发育过程中，特别是在面部间充质谱系细胞中，对典型Wnt信号传导具有冗余功能。我们的研究将为CLP的发病机制提供新的认识。反过来，这些可能转化为一种应用，通过操纵Wnt信号来预防和治疗这些常见的出生缺陷。

DESCRIPTION (provided by applicant): The long-term goal of our research is to uncover the molecular and genetic mechanisms of craniofacial birth defects in Wnt signaling mutant animal models in order to provide a basis for developing innovative prevention and therapeutic strategies. Congenital craniofacial defects, particularly the cleft lip with or without cleft palate (CLP), are among the most common birth defects in humans. CLP results from the failure of fusion in the lip or roof of the mouth during early embryonic development and has complex, but largely unknown, etiology. The canonical Wnt/ss-catenin pathway plays important roles in morphogenesis, and gene mutations in this pathway, are implicated in human genetic disease. However, the role of the canonical Wnt pathway in orofacial development, particularly in the lip and palate formation and fusion processes, remains poorly understood. We have recently found that canonical Wnt signaling is activated in the fusion sites of the orofacial primordia, and that CLP occurred in mice with a single gene mutation of Wnt signaling molecules. The mutants exhibit dramatic alterations in morphogenetic movements and candidate Wnt target genes in both facial ectoderm and mesenchyme. Therefore, we hypothesize that CLP is caused by disruption of Wnt/ss-catenin signaling pathway and its downstream targets in both facial ectoderm/epithelium and mesenchyme during lip/palate formation and fusion. Aim 1 will evaluate our hypothesis that conditional inactivation of canonical Wnt signaling in facial ectoderm will cause CLP. Aim 2 will address whether two Wnt signaling co-receptors are functional redundant for canonical Wnt signaling in development of face, particularly in the facial mesenchymal lineage cells. Our study will provide new insights into the pathogenesis and mechanisms of CLP. These in turn, may translate into an application to prevent and treat these common birth defects through manipulating Wnt signaling. PUBLIC HEALTH RELEVANCE: Congenital craniofacial defects such as cleft lip with or without cleft palate (CLP) are among the most common birth defects in humans with high prevalence and a poorly understood etiology. The current study is targeted to uncover the mechanisms of these congenital defects through genetic manipulation of the morphogenetic Wnt signaling pathway in mutant animal models, which may provide a basis for future translational applications.