Deciphering the Role of Frizzled Receptors in Palatal Development

项目总结/摘要 唇裂和/或腭裂的发病率约为1 700出生使其成为最常见的之一 先天性出生缺陷更全面地了解遗传学和信号传导机制 参与将为改善口面裂患者的治疗提供基础， 给医疗系统带来巨大负担。几种信号通路相互交叉， 腭的发育使得开发针对性疗法来治疗或预防腭裂 挑战性剖析每个通路的组成部分将提供一个更完整的图片， 腭发育Wnt信号通路是腭部发育的重要调节因子， 脑神经嵴细胞通过调节这些细胞的诱导、迁移和分化形成图案， 细胞Wnt信号还与许多调节腭架伸长的形态发生途径交叉， 提升和融合。Frizzleds（FZD）是Wnt配体的跨膜受体，并且在一些FZD中存在突变。 已经在综合征型和非综合征型唇裂患者中鉴定了10种FZD基因， 上颚具体而言，FZD 2中的杂合无义突变已在患有以下疾病的患者家族中鉴定： Robinow综合征（RS）或常染色体显性发育不良（ADO），其特征在于 包括腭裂在内的颅面畸形虽然FZD 2中的这些突变是 Fzd2杂合缺失被认为会导致单倍不足，但小鼠中Fzd2杂合缺失不会导致腭裂。我们 将使用携带RS/ADO相关突变的小鼠模型，以更好地了解FZD 2在 发育中的腭考虑到其他Wnt途径基因（WNT5A，ROR2，DVL）突变的相关性， 在RS和ADO中，我们假设这些成分与FZD 2一起信号传导以调节腭发生。 我们假设FZD 2通过非经典的WNT 5A-调节细胞迁移和上颚模式 ROR2通路，并进一步假设人RS和ADO相关的Fzd2突变主要作用于 干扰Fzd信号。为了实现这些研究目标，我们提出了以下目标：1）确定 Fzd2缺失和RS/ADO-Fzd2突变对小鼠腭发育的表型影响， 以及2）确定Fzd2调控腭发育的分子机制。中生成的数据 这项提案最终将支持开发Wnt的新治疗方法和干预措施 信号相关疾病。本文提出的这些研究计划和职业发展活动将形成一个 为我未来的独立研究打下坚实的基础。

PROJECT SUMMARY/ABSTRACT Cleft lip and/or cleft palate has an incidence of approximately 1 in 700 births making it one of the most common congenital birth defects. Gaining a more complete understanding of the genetics and signaling mechanisms involved will provide a foundation for improving treatment of patients with orofacial clefts, ultimately reducing an enormous burden on the healthcare system. Several signaling pathways intersect to regulate the proper development of the palate which makes developing targeted therapies to treat or prevent cleft palate challenging. Dissecting the components of each pathway involved will provide a more complete picture of palatogenesis. The Wnt signaling pathway is an important regulator of palatal development and regulates early patterning by cranial neural crest cells through regulation of induction, migration, and differentiation of these cells. Wnt signaling also intersects many morphogenic pathways that regulate palatal shelf elongation, elevation, and fusion. Frizzleds (FZDs) are transmembrane receptors for Wnt ligands and mutations in some of the 10 FZD genes have been identified in patients with both syndromic and non-syndromic cleft lip and/or palate. Specifically, heterozygous nonsense mutations in FZD2 have been identified in patient families with Robinow Syndrome (RS) or Autosomal Dominant Omodysplasia (ADO), syndromes which are characterized by limb reductions and craniofacial anomalies including cleft palate. While these mutations in FZD2 were thought to cause haploinsufficiency, heterozygous deletion of Fzd2 in mice does not lead to cleft palate. We will use mouse models harboring RS/ADO-associated mutations to better understand how FZD2 functions in the developing palate. Given the association of mutations in other Wnt pathway genes (WNT5A, ROR2, DVL) in RS and ADO, we hypothesize that these components signal together with FZD2 to regulate palatogenesis. We hypothesize that FZD2 regulates cell migration and palatal patterning through a non-canonical WNT5A- ROR2 pathway and further hypothesize that human RS- and ADO-associated Fzd2 mutations act dominantly to interfere with Fzd signaling. To achieve these research goals, we propose the following aims: 1) determine the phenotypic consequences of Fzd2 deletion and RS/ADO-Fzd2 mutations on palatal development in mice, and 2) determine the molecular mechanisms behind Fzd2 regulation of palate development. Data generated in this proposal will ultimately support the development of novel therapeutic approaches and interventions in Wnt signaling-related diseases. These research plan and career development activities proposed here will form a solid basis for my future independent research program.