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.

项目概要/摘要 虽然唇裂（伴或不伴腭裂）是最常见的颅面出生缺陷之一，但分子生物学 该表型的细胞病因学尚不完全清楚，并且其基本形态发生 上唇形成的基础在很大程度上仍然是个谜。这部分是由于复杂的三维 妊娠中期几天内发育中面的拓扑结构。唇部开始时 发育过程中，额鼻突（FNP）颅外胚层发生显着的形态变化 从双侧鼻上皮基板增厚和形成开始，鼻基板发生内陷 形成鼻凹，将内侧鼻突（MNP）与外侧鼻突（LNP）分开。融合 MNP 和 LNP 包围鼻道并启动上唇的形成，这也涉及 MNP 和上颌突 (MXP) 的融合。虽然一些研究重点关注这些 在最后的融合步骤中，对细胞驱动器和分子调节器的关注要少得多 在鼻凹形成过程中发生显着的先前形态变化，因为它有助于正确的唇部形成。 之前的报告以及此处提供的初步数据表明，TGFβ 受体 I (Alk5) 的丢失 颅面外胚层内的病变导致唇裂。通过 TGFβRI 的 TGFβ 信号传导可以激活经典和/或 以上下文特定的方式非规范下游信号传导途径，导致转录和/或 细胞骨架的变化在许多组织形态发生事件中至关重要。 TGFβRI 或肌动球蛋白的破坏 通过两种主要哺乳动物胚胎非肌肉肌球蛋白 NMIIA 和 NMIIA 的复合损失来抑制收缩力 NMIIB，导致唇裂和早期鼻凹形态发生缺陷。 该项目将测试中心假设，即鼻凹形态发生部分是由组织弯曲驱动的 通过肌动球蛋白收缩性，引起构象变化，使 MNP/LNP/MXP 接近融合 并建立中面部结构，而通过 TGFβRI 的信号传导是该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，因为它有助于唇部形成。目标2将 确定 TGFβ 信号如何通过 TGFβRI 驱动鼻凹形态发生和唇部形成。这项研究将 这是了解上唇形态发生如何发生以及唇裂潜在机制的关键一步。