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; 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.

形态发生需要仔细跨多个维度进行调节，以确保正确定位和身份 分化的祖细胞。最终，区分细胞必须协调多个物理参数 - 他们的环境，位置，扩散和形状 - 并使用这些提示来告知其最终状态和功能。 一种这种细胞形状的变化广泛用于产生复杂的组织结构是根尖的收缩： 细胞顶端结构域的收缩变成楔形。顶部狭窄累积驱动器 在各种关键发育过程中的组织形状变化，包括胃和分支 形态发生。我们对顶端的物理和调节特征学到的大多数 收缩来自非哺乳动物模型生物，主要是无脊椎动物。是否哺乳动物组织 使用保守或独特的根尖收缩机制和机械尚未阐明，也不清楚 如何在多个不同的发育中灵活地使用这种保守的生物物理现象 过渡。尽管顶端收缩机械通常在同一保守蛋白上收敛，但 时尚动力学在上下文和物种之间差异很大。我们旨在确定直接的蛋白质 哺乳动物的顶端收缩，定义其时空动力学，并连接该途径的诱导 核心遗传驱动因素。我们将发现确保鲁棒性和机械完整性的一般原则 通过检查顶端收缩是基本形态学特征的多种发育环境。 在接下来的五年中，我们将解决细胞形状如何改变并通过 回答以下问题：1）哪种力培养机制驱动哺乳动物的根尖收缩？ 2）哪些分子机制调节顶端收缩期间皮质重组？ 3）如何 发育细胞命运过渡许可证的身体形状的物理方面？确保我们的发现可以广泛 广义，我们将调查顶端收缩至关重要的多个系统，包括主要系统 肠细胞培养和早期小鼠胚胎。具体而言，我们在肠道隐窝中对顶点收缩进行建模 形成，原始条纹形成和神经管形成。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之一的机制，识别 指导该过程的新因素，并将细胞状态的调节与基本物理特征联系起来。 这些知识将共同建立对哺乳动物组织如何坐标的基本理解 形态发生。拟议的项目与我的研究小组的长期愿景保持一致，以定义细胞 控制组织模式的机制，以了解建筑如何调节细胞命运和行为。