The role of Hippo signaling in palate development

项目总结 继发性腭裂是最常见的先天性畸形之一，患病率为1/1500 活产。患有腭裂的人可以由专家团队按照功能和审美标准进行治疗； 然而，目前的治疗需要在一生中进行多次手术，这与显著的 因此，有机会改进治疗方法和结果。加深了解 关于腭裂发生的生物学过程的研究将为改进干预措施提供一个基础 并将为腭裂患者建立治疗方案。 继发性上颌骨发育是一个复杂的、多步骤的过程，在这个过程中，腭架从 上颌突与发育中的舌部垂直、侧向生长。然后，腭架重新定位 进入舌背的水平位置，这一过程被称为腭架抬高。货架越来越大 水平地在中线相遇并融合，形成分隔口腔和鼻部的软硬腭 龋齿。腭架抬高的过程是腭裂发生过程中最不被了解的一个方面。 在腭架过程中，腭架的组织张力和形态发生了巨大的变化 然而，张力是如何产生并由细胞解释以导致组织重塑的 明白了。 河马途径是新近发现的一种调节器官大小和组织的机械感觉途径 通过控制增殖、凋亡和分化来修复。河马路径的下游目标， YAP和带有PDZ结合基序的转录共激活因子(TAZ)，转位到 细胞核和调节基因转录以响应细胞几何形状的变化，细胞外基质(ECM) 僵硬和身体伸展。为了探索张力和细胞形态变化之间的联系 腭架在抬高过程中，这项建议调查河马信号通路在二次腭部 队形。 次级腭间充质细胞亚群中YAP和Taz的缺失会导致腭裂， 具体地说，是腭架抬高的缺陷。这项研究提案将确定YAP/TAZ在以下方面的作用 并测试YAP/TAZ是由腭架上的张力激活的假设， 由细胞外基质和细胞骨架重塑产生，以诱导上调所需的基因转录。目标1将 分析缺失YAP和Taz的腭间充质的变化并确定河马的作用 腭裂发生中的信号传递。目的2建立YAP/TAZ在上颌骨中作用的分子机制 通过确定YAP/TAZ的转录靶点进行研究。这项工作将带来新的洞察力 腭升高下的物理和细胞生物学将拓宽我们对腭裂发生的理解 以及继发性腭裂，指导未来对腭裂患者的治疗。

PROJECT SUMMARY Clefting of the secondary palate is one of the most common congenital anomalies, with a prevalence of 1/1,500 live births. Individuals with cleft palate can be treated by a team of specialists to functional and esthetic norms; however, the current treatment requires multiple surgeries throughout life, which are associated with significant morbidities, and thus, there is an opportunity to improve therapies and outcomes. An increased understanding of the biological processes underlying palatogenesis will provide a foundation on which improved interventions and therapies will be built for patients with cleft palate. Secondary palate development is a complex, multi-step process in which the palatal shelves develop from the maxillary processes and grow vertically, lateral to the developing tongue. The palatal shelves then reorient into a horizontal position dorsal to the tongue in a process termed palatal shelf elevation. The shelves grow horizontally to meet at the midline and fuse to form the hard and soft palate that separate the oral and nasal cavities. The process of palatal shelf elevation is one of the least understood aspects of palatogenesis. Tremendous change in tissue tension and morphology occurs in the palatal shelves during palatal shelf elevation, yet how tension is generated and interpreted by the cells to result in tissue remodeling is not understood. The Hippo pathway is a recently discovered mechanosensory pathway that regulates organ size and tissue repair by controlling proliferation, apoptosis, and differentiation. The downstream targets of the Hippo pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), translocate to the nucleus and regulate gene transcription in response to change in cell geometry, extracellular matrix (ECM) stiffening, and physical stretching. In order to probe for a link between tension and morphological change in the palatal shelves during elevation, this proposal investigates the Hippo signaling pathway in secondary palate formation. Deletion of Yap and Taz in a subset of secondary palate mesenchymal cells results in cleft palate and, specifically, defects in palatal shelf elevation. This research proposal will determine the role of YAP/TAZ in palatal shelf elevation and test the hypothesis that YAP/TAZ are activated by tension in the palatal shelves, created by ECM and cytoskeleton remodeling, to induce gene transcription required for elevation. Aim 1 will analyze changes in the palatal mesenchyme with deletion of Yap and Taz and determine the role of Hippo signaling in palatogenesis. Aim 2 will establish the molecular mechanism of action of YAP/TAZ in palate development by determining transcriptional targets of YAP/TAZ. This work will bring new insight into the physical and cellular biology underlying palate elevation that will broaden our understanding of palatogenesis and clefting of the secondary palate, guiding future therapies for patients with cleft palate.