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，以确保正确的位置和身份 分化祖细胞的能力。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--并使用这些线索来告知它们的最终状态和功能。 一种广泛用于产生复杂组织结构的细胞形状变化是根尖收缩： 细胞顶端结构域缩小为楔形。根尖狭窄累积性驱动 组织形态在各种关键发育过程中的变化，包括原肠形成和分枝 形态发生。我们所了解的大多数关于心尖部的物理和调节特征 收缩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 使用保守的或独特的根尖收缩机制和机制尚未阐明，也不清楚 这种保守的生物物理现象如何在多种不同的发育过程中如此灵活地利用 过渡。尽管顶端收缩机制通常集中在相同的保守蛋白质上，但它们的 时空动态在不同的环境和物种中差异很大。我们的目标是找出能引导 哺乳动物的心尖收缩，定义它们的时空动力学，并连接这一途径的诱导 核心基因驱动因素。我们将揭示确保健壮性和机械完整性的一般原则 通过检查不同的发育环境，其中顶端收缩是基本的形态发生特征。 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 回答以下问题：1)是什么力量产生机制驱动哺乳动物的心尖收缩？ 2)什么分子机制调节根尖收缩过程中的皮质重组？3)如何 发育中的细胞命运转换许可细胞形状的物理方面？以确保我们的发现可以广泛地 一般说来，我们将研究根尖收缩是必要的多个系统，包括初级 肠道细胞培养和小鼠早期胚胎。具体地说，我们模拟了肠隐窝的心尖收缩。 形成、原始条纹形成和神经管形成。这些系统将允许我们调查 哺乳动物根尖收缩的动力学、关键机械部件的定位、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 深入了解推动最广泛使用的形态发生细胞形状变化之一的机制，确定 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。 总而言之，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。建议的项目与我的研究小组定义细胞的长期愿景一致 控制组织模式的机制，以了解结构如何调节细胞的命运和行为。