The regulation and cellular dynamics of neural crest cell delamination in mammalian craniofacial development

项目摘要 颅面畸形占人类所有先天出生缺陷的三分之一，并对 国家医疗保健预算。受影响的人通常在他们的一生中接受多次手术， 很少是完全矫正的。因此，开发改善预后和改善预后的治疗方法至关重要。 预防，但这只能来自于对遗传和细胞机制的更好理解 主宰头面部发育和个体疾病的病因和发病机制。中途中断 神经脊细胞(NCC)的发育被认为是许多头面部出生缺陷的潜在原因。 因此，了解调控NCC发育的遗传和细胞机制及其 最终生成的头面部组织对开发预防性治疗和改进外科手术至关重要 预后。 神经上皮细胞的剥离是移行性NCC形成的关键步骤。然而， 哺乳动物胚胎中NCC分层的分子和细胞机制尚不清楚。 明白了。分层是细胞离开其组织环境的生物物理过程，而我的 大量的初步数据表明，细胞挤出可能是促进颅骨NCC的一种新机制 分层。这项建议侧重于细胞挤压，并将拓宽我们对NCC分层的理解 通过阐明通过细胞挤出调节NCC分层的细胞和遗传系统。Aim1将 可视化并捕捉驱动颅骨NCC的动态细胞结构和形态变化 小鼠胚胎的分层。AIM2将研究Piezo1，一种机械敏感的离子通道在 颅骨NCC分层与颅面发育。Piezo1功能丧失对NCC的影响 分层和颅面发育将通过零基因和条件基因敲除进行分析 PIEZO1在小鼠胚胎中的机械敏感离子通道。下游调控网络和信令 然后，将通过转录比较来阐明途径，以测量候选基因的差异 下游调控因子介于野生型和敲除胚胎之间。这项研究的完成将提前 基本知识和对神经脊细胞和颅面发育的进一步了解 先天出生缺陷。

Project Summary Craniofacial anomalies account for a third of all human congenital birth defects and significantly impact national health care budgets. Affected individuals typically undergo multiple surgeries throughout their lifetime, which are rarely fully corrective. Therefore, it is critical to develop therapies for improved prognosis and prevention, but this can only come from a better understanding of the genetic and cellular mechanisms governing craniofacial development and the etiology and pathogenesis of individual disorders. Disruptions in neural crest cell (NCC) development are considered the underlying cause of many craniofacial birth defects. Therefore, understanding the genetic and cellular mechanisms that regulate NCC development and their ultimate generation of craniofacial tissue is crucial for developing preventative therapies and improved surgical prognosis. Delamination from the neuroepithelium is a critical step in the formation of migrating NCC. However, the molecular and cellular mechanisms governing NCC delamination in mammalian embryos are poorly understood. Delamination is a biophysical process by which a cell departs its tissue environment, and my extensive preliminary data indicates that cell extrusion may be a novel mechanism facilitating cranial NCC delamination. This proposal focuses on cell extrusion and will broaden our understanding of NCC delamination by elucidating the cellular and genetic systems regulating NCC delamination via cell extrusion. Aim1 will visualize and capture the dynamic cytoarchitectural and morphological changes that drive cranial NCC delamination in mouse embryos. Aim2 will investigate the role of Piezo1, a mechanosensitive ion channel in cranial NCC delamination and craniofacial development. The impact of Piezo1 loss-of-function on NCC delamination and craniofacial development will be analyzed through null and conditional genetic knock out of Piezo1 mechanosensitive ion channels in mouse embryos. The downstream regulatory network and signaling pathways will then be elucidated through transcriptomic comparisons measuring the differences in candidate downstream regulators between wild type and knock out embryos. Completion of the study will advance fundamental knowledge and further our understanding of neural crest cell and craniofacial development and of congenital birth defects.