Mechanisms of cellular morphogenesis that coordinate signaling during tissue patterning

项目摘要 我们研究计划的长期目标是了解和确定细胞形状的机制 动力学，其促进来自局部细胞-细胞通信事件的组织范围模式的出现。的 通过干扰信号传导对基因和细胞行为的不正确的空间和时间诱导可导致 发展中的重大失误。因此，了解信号传导机制是如何发挥作用的至关重要。 在细胞或相邻细胞水平上的位置在更大的组织长度尺度上协调， 模式和支持组织稳态。细胞丝，或信号丝状伪足，是长的富含肌动蛋白的细胞 突起允许细胞与一定距离处的其他细胞物理相互作用并向其发送信号。蜂窝 像细胞丝这样的突起已经被证明在许多发育过程中发挥作用，包括斑点 和条纹图案化、肢体图案化、干细胞小生境维持和神经板图案化。尽管如此， 对调节细胞丝特异性形成和行为的一般机制知之甚少。 我们感兴趣的是了解这些突起是如何在细胞骨架水平上受到调节的， 机制，并作为细胞范围和组织范围的信号状态的一个组成部分。为了解决这个 问题，我们使用果蝇（Drosophila melanogaster）背胸上刚毛的斑点图案作为 模型系统在鬃毛图案形成期间，细胞丝从胸部上皮细胞的基底表面延伸， 促进长距离Notch介导的侧抑制。利用我们在果蝇模型系统方面的优势 遗传学和定量活体显微镜，在未来五年内，我们的目标包括了解 细胞素的形成受到调节，特别是Notch介导的侧抑制信号传导的下游。在 与此同时，我们的目标是了解细胞丝活动如何有助于细胞和组织的异质性， 有利于及时形成组织良好的模式。这些研究不仅会产生有价值的细胞 关于细胞素的具体调节的生物学知识，但也将阐明基本的 在长度尺度上协调图案的机制。

Project Summary The long-term goal of our research program is to understand and identify the mechanisms of cell shape dynamics that facilitate the emergence of tissue-wide patterns from local cell-cell communication events. The incorrect spatial and temporal induction of genes and cell behaviors by perturbed signaling can lead to catastrophic errors in development. Therefore, it is critical to understand how signaling mechanisms that take place at the level of a cell or adjacent cells are coordinated across larger tissue length scales to achieve robust patterns and support tissue homeostasis. Cytonemes, or signaling filopodia, are long actin-rich cellular protrusions that allow cells to physically interact with, and signal to, other cells at a distance. Cellular protrusions like cytonemes have been shown to play a role in many developmental processes, including spot and stripe patterning, limb patterning, stem cell niche maintenance, and neural plate patterning. Despite this, relatively little is known about the general mechanisms that regulate cytoneme-specific formation and behavior. We are interested in understanding how these protrusions are regulated both at the level of cytoskeletal mechanisms, and as an integrated part of the cell-wide and tissue-wide signaling states. To address this problem, we use the spot pattern of bristles on the dorsal thorax of the fruit fly Drosophila melanogaster as a model system. During bristle patterning, cytonemes extend from the basal surface of thoracic epithelial cells to facilitate long-range, Notch-mediated, lateral inhibition. Leveraging our strengths in Drosophila model systems genetics and quantitative live microscopy, over the next five years our goals include understanding how the formation of cytonemes are regulated, especially downstream of Notch-mediated lateral inhibition signaling. In parallel, we aim to understand how cytoneme activity contributes to cell and tissue heterogeneities that facilitate the timely formation of well-organized patterns. These studies will not only yield valuable cell biological knowledge about the specific regulation of cytonemes, but will also elucidate fundamental mechanisms that coordinate patterning across length scales.