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

鼻凹形态发生的分子基础及其在上唇形成中的作用

• 批准号: 10824138
• 负责人: Luke David Lucido
• 金额: $ 4.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10824138
• 关键词: 3-Dimensional; Ablation; Actomyosin; Apical; Attention; Automobile Driving; Bilateral; Cell Polarity; Cell Proliferation; Cell Shape; Cells; Cellular Assay; Cephalic; Chemicals; Cleft Lip; Cleft lip with or without cleft palate; Complex; Congenital Abnormality; Cytoskeleton; Data; Defect; Development; Ectoderm; Embryo; Epithelial Cells; Epithelium; Etiology; Event; F-Actin; Failure; Genetic Transcription; Growth; Lateral; Ligands; Light; Lip structure; Maxilla; Medial; Mesenchyme; Microfilaments; Modeling; Molecular; Molecular Conformation; Morphogenesis; Morphology; Movement; Mus; Myosin ATPase; Nasal Epithelium; Nose; Outcome; Output; Phenotype; Phosphorylation; Pregnancy; Process; Proliferating; Regulation; Reporting; Role; Series; Shapes; Signal Pathway; Signal Transduction; Specificity; Structural Congenital Anomalies; Structure; Testing; Three-Dimensional Imaging; Time; Tissues; Transforming Growth Factor beta; Visualization; With laterality; constriction; craniofacial; experimental study; lip morphogenesis; malformation; mutant; nestin protein; non-muscle myosin; prevent; receptor

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.

项目总结/摘要 虽然唇裂，有或没有腭裂，是最常见的颅面出生缺陷之一， 表型的细胞病因学还不完全清楚， 上唇的形成仍然是个谜这部分是由于复杂的三维 在妊娠中期的一系列几天内，发育中面的拓扑结构。在唇缘开始时 在发育过程中，额鼻突（FNP）颅外胚层经历了实质性的形态变化 从两侧增厚和上皮鼻基板的形成开始，鼻基板经历内陷， 形成鼻凹，将内侧鼻突（MNP）与外侧鼻突（LNP）分开。融合 MNP和LNP包围鼻管并启动上唇的形成，这也涉及 MNP和上颌突融合（MXP）。虽然一些研究集中在这些调节 在最后的融合步骤中，很少注意到细胞驱动因子和分子调节因子的作用。 在鼻小凹形成过程中的重要的先前形态变化，因为它有助于适当的嘴唇形成。 先前的报道以及本文提供的初步数据表明，TGFβ受体I（Alk 5）的缺失 导致唇裂通过TGFβRI的TGFβ信号转导可以激活经典和/或 非典型的下游信号传导途径，以特定的方式，导致转录和/或 在许多组织形态发生事件中至关重要的细胞骨架变化。TGFβRI或肌动球蛋白的破坏 通过两种主要的哺乳动物胚胎非肌肉肌球蛋白NMIIA和 NMIIB导致唇裂和早期鼻小凹形态发生缺陷。 这个项目将测试中心的假设，鼻小凹形态，驱动部分由组织弯曲驱动 通过肌动球蛋白收缩性，引起构象变化，使MNP/LNP/MXP接近融合 并建立面中部结构，通过TGFβRI的信号传导是这一过程的关键调节因子。目标1将 建立驱动鼻凹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TGFβ信号如何通过TGFβRI驱动鼻小凹形态发生和嘴唇形成。本研究将 这是理解上唇形态发生和唇裂机制的关键一步。