Mechanics of mammalian morphogenesis

哺乳动物形态发生的机制

• 批准号: 10711987
• 负责人: Kaelyn D. Sumigray
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711987
• 关键词: Apical; Architecture; Automobile Driving; Behavior; Biophysics; Cell Culture Techniques; Cell Differentiation process; Cell Shape; Cells; Complex; Cues; Development; Developmental Process; Dimensions; Disparate; Embryo; Ensure; Environment; Event; Genetic; Genetic Transcription; Intestines; Invertebrates; Investigation; Knowledge; Learning; Licensing; Mammals; Mechanics; Modeling; Molecular; Morphogenesis; Movement; Mus; Neural tube; Pathway interactions; Pattern; Positioning Attribute; Primitive Streaks; Process; Proliferating; Proteins; Regulation; Research; Shapes; System; Tissues; constriction; flexibility; gastrulation; insight; intestinal crypt; model organism; novel; protein protein interaction; spatiotemporal; stem cells

Morphogenesis requires careful regulation across multiple dimensions to ensure proper positioning and identity of differentiating progenitor cells. Ultimately, differentiating cells must coordinate multiple physical parameters - their environment, position, proliferation and shape - and use these cues to inform their final state and function. One such cellular shape change broadly utilized to produce complex tissue architectures is apical constriction: the shrinkage of the apical domain of cells to become wedge-shaped. Apical constriction cumulatively drives tissue shape changes during various key developmental processes, including gastrulation and branching morphogenesis. The majority of what we have learned about the physical and regulatory features of apical constriction come from non-mammalian model organisms, primarily invertebrates. Whether mammalian tissues use conserved or distinct apical constriction mechanisms and machinery has not been elucidated, nor is it clear how this conserved biophysical phenomenon can be so flexibly utilized across multiple disparate developmental transitions. Although apical constriction machinery generally converges on the same conserved proteins, their spatiotemporal dynamics vary widely across contexts and species. We aim to identify the proteins that direct mammalian apical constriction, define their spatiotemporal dynamics, and connect the induction of this pathway to core genetic drivers. We will uncover the general principles that ensure robustness and mechanical integrity by examining diverse developmental contexts where apical constriction is a fundamental morphogenic feature. Over the next five years, we will address how cell shape changes initiate and control morphogenesis by answering the following questions: 1) What force-generating mechanisms drive mammalian apical constriction? 2) What molecular mechanisms regulate cortical reorganization during apical constriction? 3) How do developmental cell fate transitions license physical aspects of cell shape? To ensure our findings can be broadly generalized, we will investigate multiple systems where apical constriction is essential, including primary intestinal cell culture and the early mouse embryo. Specifically, we model apical constriction in intestinal crypt formation, primitive streak formation and neural tube formation. These systems will allow us to investigate the dynamics of mammalian apical constriction, localization of key machinery components, protein-protein interactions, and the transcriptional networks that control the timing of their induction. These studies will produce deep insight into the mechanisms driving one of the most widely used morphogenetic cell shape changes, identify novel factors that direct the process, and connect the regulation of cell state to essential physical features. Together, this knowledge will establish a fundamental understanding of how mammalian tissues coordinate morphogenesis. The proposed project aligns with my research group's long-term vision to define cellular mechanisms controlling tissue patterns to understand how architecture regulates cell fates and behaviors.

形态发生需要在多个维度上进行仔细的调节，以确保正确的定位和身份 分化的祖细胞。最终，分化细胞必须协调多个物理参数- 它们的环境、位置、增殖和形状--并利用这些线索来告知它们的最终状态和功能。 广泛用于产生复杂组织结构的一种这样的细胞形状变化是顶端收缩： 细胞顶端区域收缩成楔形。心尖收缩累积驱动 在各种关键的发育过程中，包括原肠胚形成和分支， 形态发生我们所了解的关于根尖细胞的物理和调节特征的大部分内容， 缩窄来自非哺乳动物模式生物，主要是无脊椎动物。哺乳动物组织是否 使用保守的或不同的顶端缢痕机制和机械尚未阐明，也不清楚 这种保守的生物物理现象如何能够在多种不同的发育过程中如此灵活地利用， 过渡。虽然顶端缢缩机制通常集中在相同的保守蛋白质上，但它们的 时空动态因环境和物种而异。我们的目标是鉴定出 哺乳动物顶端收缩，定义其时空动态，并连接该途径的诱导 to core核心genetic遗传drivers驱动.我们将揭示确保坚固性和机械完整性的一般原则 通过研究不同的发展背景，顶端收缩是一个基本的形态特征。 在接下来的五年里，我们将通过以下方式解决细胞形状变化如何启动和控制形态发生的问题： 回答以下问题：1）什么样的力产生机制驱动哺乳动物顶端收缩？ 2)什么样的分子机制调节皮层重组在顶端收缩？3)怎么 发育细胞命运的转变许可细胞形状的物理方面？为了确保我们的发现能够广泛地 广义上，我们将研究多个系统，其中顶端收缩是必不可少的，包括原发性 肠细胞培养和小鼠早期胚胎。具体来说，我们在肠隐窝中模拟顶端收缩， 形成、原条形成和神经管形成。这些系统将使我们能够调查 哺乳动物顶端收缩的动力学，关键机械组件的定位，蛋白质-蛋白质 相互作用，以及控制其诱导时间的转录网络。这些研究将产生 深入了解驱动最广泛使用的形态发生细胞形状变化的机制， 指导这一过程的新因素，并将细胞状态的调节与基本的物理特征联系起来。 总之，这些知识将建立对哺乳动物组织如何协调的基本理解 形态发生拟议的项目与我的研究小组定义蜂窝的长期愿景一致 控制组织模式的机制，以了解结构如何调节细胞命运和行为。