The Molecular Basis of Nasal Pit Morphogenesis and its Role in Upper Lip Formation

项目摘要/摘要 而唇裂，无论有没有腭裂，都是最常见的头面部出生缺陷之一，分子 而表型的细胞病因学还不完全清楚，而基本的形态发生 上唇的形成在很大程度上仍然是个谜。这在一定程度上是由于复杂的三维 妊娠中期连续几天的面中部发育的拓扑图。在嘴唇开始的时候 额鼻突(FNP)颅骨外胚层的发育经历了实质性的形态变化 开始于双侧鼻腔上皮细胞的增厚和形成，这经历了内陷到 形成鼻窝，将内侧鼻突(MNP)和外侧鼻突(LNP)分开。融合 MNP和LNP包围鼻道，启动上唇的形成，这也涉及到 MNP与上颌突融合(MXP)。虽然一些研究集中在对这些物质的调节上 最后的融合步骤，对细胞驱动器和分子调节器的关注要少得多。 在鼻窝形成过程中有重要的先前形态变化，因为它有助于正确的嘴唇形成。 以前的报告和这里提供的初步数据表明，转化生长因子β受体I(ALK5)的丢失 在头面部内，外胚层会导致唇裂。转化生长因子β信号通过转化生长因子βRI激活规范和/或 以上下文特定的方式非规范的下游信号通路，导致转录和/或 细胞骨架改变在许多组织形态发生事件中起关键作用。阻断转化生长因子βRI或肌动球蛋白 两种主要的哺乳动物胚胎非肌肉肌球蛋白NMIIA和NMIIA的复合丧失所致的收缩能力 NMIIB，导致唇裂和早期鼻窝形态发生缺陷。 该项目将检验鼻窝形态发生的中心假设，即部分由组织弯曲驱动 通过肌动球蛋白的收缩，导致构象变化，使MNP/LNP/MXP接近融合 并建立面中部结构，通过转化生长因子βRI的信号是这一过程的关键调节因子。目标1将 建立推动鼻窝形态发生的细胞动力学，因为它有助于嘴唇的形成。目标2将 确定转化生长因子β信号通过转化生长因子βRI如何驱动鼻窝形态发生和嘴唇形成。这项研究将是 这是理解上唇形态发生的关键一步，也是理解唇裂发生机制的关键一步。

Project Summary/Abstract While cleft lip, with or without cleft palate, is one of the most common craniofacial birth defects, the molecular and cellular etiology of the phenotype is incompletely understood, and the fundamental morphogenesis that underlies upper lip formation remains largely mysterious. This is in part due to a complex three-dimensional topology of the developing midface over a series of several days during mid-gestation. At the onset of lip development, the frontonasal process (FNP) cranial ectoderm undergoes substantial morphological change starting with bilateral thickening and formation of the epithelial nasal placodes, which undergo invagination to form nasal pits, separating the medial nasal processes (MNP) from the lateral nasal processes (LNP). Fusion of the MNP and the LNP encloses the nasal canals and initiates the formation of the upper lip, which also involves fusion of the MNP and maxillary process (MXP). While some studies have focused on the regulation of these final fusion steps, much less attention has been paid to the cellular drivers and molecular regulators of the significant preceding morphologic changes during nasal pit formation as it contributes to proper lip formation. Previous reports together with preliminary data presented here, demonstrate that loss of TGFβ Receptor I (Alk5) within the craniofacial ectoderm leads to cleft lip. TGFβ signaling via TGFβRI can activate both canonical and/or noncanonical downstream signaling pathways in a context specific manner, leading to transcriptional and/or cytoskeletal changes critical in many tissue morphogenesis events. Disruption of TGFβRI or actomyosin contractility through the compound loss of the two major mammalian embryonic non-muscle myosins, NMIIA and NMIIB, results in cleft lip and defects in early nasal pit morphogenesis. This project will test the central hypothesis that nasal pit morphogenesis, driven in part by tissue bending driven by actomyosin contractility, causes conformational changes that bring the MNP/LNP/MXP in proximity for fusion and establish midface structure, and that signaling via TGFβRI is a key regulator of this process. Aim 1 will establish the cellular dynamics driving nasal pit morphogenesis as it contributes to lip formation. Aim 2 will determine how TGFβ signaling via TGFβRI drives nasal pit morphogenesis and lip formation. This study will be a key step in understanding how upper lip morphogenesis occurs, and the mechanisms underlying cleft lip.