Deciphering the Role of Frizzled Receptors in Palatal Development

项目摘要/摘要 唇裂和/或腭裂的发病率约为每700名新生儿中就有1名，使其成为最常见的 先天出生缺陷。对遗传学和信号机制有了更全面的了解 这将为改善口腔裂隙患者的治疗提供基础，最终减少 这给医疗体系带来了巨大的负担。几条信号通路相交以调节适当的 开发治疗或预防腭裂的靶向疗法的腭裂的发展 很有挑战性。解剖所涉及的每一条途径的组成部分将提供更完整的图景 腭裂。Wnt信号通路是腭部发育的重要调节因子，对早期发育具有调节作用 颅神经脊细胞通过对这些细胞的诱导、迁移和分化的调节而形成图案 细胞。WNT信号还与许多调节腭架伸长的形态发生通路相交， 升空和融合。Frizzleds(FZD)是Wnt配体的跨膜受体，在一些 已在综合征性和非综合征性唇裂和/或唇裂患者中发现了10个FZD基因 味觉。具体地说，FZD2杂合无义突变已在患者家族中被发现 Robinow综合征(RS)或常染色体显性遗传性卵泡发育不良(ADO) 通过截肢和包括腭裂在内的颅面畸形。而FZD2的这些突变是 Fzd2杂合缺失被认为会导致单倍体功能不全，但不会导致腭裂。我们 将使用携带RS/ADO相关突变的小鼠模型来更好地了解FZD2在 发展中的味觉。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FZD2一起发出信号来调节腭裂的发生。 我们推测FZD2通过非规范的Wnt5A调控细胞迁移和腭纹形成- ROR2途径，并进一步假设人类RS和ADO相关的Fzd2突变起主导作用 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突变对小鼠腭部发育的表型影响， 2)确定Fzd2调控腭部发育的分子机制。生成的数据在 这项提议最终将支持WNT新的治疗方法和干预措施的发展 与信号相关的疾病。这些在这里提出的研究计划和职业发展活动将形成 为我未来的独立研究项目奠定了坚实的基础。

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.