Morphogenesis: Biophysics and Genetics of Dorsal Closure

细胞片形态发生在脊椎动物形态发生过程中的发育里程碑中起着至关重要的作用， 包括原肠胚形成以及神经管、心脏和腭的形成。这对于 伤口愈合。协调细胞机制和驱动和调节的信号级联 形态发生至关重要——失调会导致发育和伤口愈合缺陷，这可能是致命的。 我们专注于细胞片层形态发生如何被驱动、调节和协调的基础生物学 在果蝇的背部闭合期间。分子、细胞和组织结构的保护 使闭合成为探究形态发生的分子基础的理想模型系统。 在闭合过程中，侧表皮片前进以闭合背侧开口。封闭适用于多种情况 多种实验方法的结合，我们开创了将封闭作为模型系统的研究，特别是通过 使用实时成像策略。我们确定了有助于结束的四个流程，并证明了 绝对不需要任何单一力量的贡献。因此，闭包是稳健的、有弹性的和冗余的 在后生动物系统发育中保守的分子成分。我们最近的工作重点是离子通量如何 有助于闭合并提出了一个热力学模型来理解闭合过程中的组织重塑。我们 解决来自图案和极性基因产物的信号如何汇聚以调节细胞形状和变化 表征形态发生的细胞形状。我们发起了一项正向遗传筛选，直接评估 闭合的运动学并研究闭合的稳健性和弹性的遗传基础。超过140个 之前已知基因对 DC 有贡献，我们已经发现了 23 个额外的遗传区间 在仅 1/? 的试点屏幕中关闭所需的数量？果蝇基因组。我们计划在未来五年内 使用基因发现来识别闭合所需的新基因。我们将使用高分辨率 4D 成像 定量记录表征野生型和突变动物闭合特征的细胞形状变化， 然后使用生物物理策略来确定这些新基因如何促进力量的产生和调节 的关闭。我们计划解决的关键概念差距是胚胎模式在建立 表征胚胎闭合开始时的细胞和亚细胞结构以及离子流动方式 有助于关闭。我们将调查触发关闭和反馈开始的信号（或多个信号） 补偿闭合过程中遗传或身体损伤的机制。我们将继续 探索产生力的细胞骨架成分如何定位、协调和调节，并研究如何 粘附复合物既传递力又允许细胞运动。 我们有独特的能力来解决表征细胞片层基本生物学特征的现有关键问题 果蝇的形态发生。由于形态发生在分子、细胞和组织水平上高度保守， 我们的工作直接影响脊椎动物发育和伤口愈合中的形态发生。

Cell sheet morphogenesis plays crucial roles in developmental milestones during vertebrate morphogenesis, including gastrulation and the formation of the neural tube, the heart, and the palate. It is also essential for wound healing. Coordination of the cellular machineries and the signaling cascades that drive and regulate morphogenesis is critical – misregulation results in developmental and wound healing defects that can be fatal. We focus on the fundamental biology of how cell sheet morphogenesis is powered, regulated and coordinated during dorsal closure in Drosophila melanogaster. Conservation of molecular, cellular and tissue archictecture make closure an ideal model system for interrogating the molecular basis of morphogenesis. During closure, lateral epidermal sheets advance to close a dorsal opening. Closure is amenable to a wide variety of diverse experimental approaches and we pioneered the study of closure as a model system, especially through the use of live imaging strategies. We identified four processes that contribute to closure and demonstrated that no single force that contributes is absolutely required. Thus, closure is robust, resilient and redundant using molecular components that are conserved across metazoan phylogeny. Our recent work focuses on how ion fluxes contribute to closure and proposes a thermodynamic model to understand tissue remodeling during closure. We address how signals from patterning and polarity gene products converge to regulate cell shape and the changes in cell shape that characterize morphogenesis. We initiated a forward genetic screen that directly assesses the kinematics of closure and investigates the genetic basis for closure's robustness and resilience. More than 140 genes were previously known to contribute to DC and we have already discovered 23 additional genetic intervals that are required for closure in a pilot screen of just ¹/? of the fly genome. During the next five years we plan to use gene discovery to identify new genes that are required for closure. We will use high-resolution 4D imaging to document quantitatively the cellular shape changes that characterize closure in wild type and mutant animals, then use biophysical strategies to determine how these new genes contribute to force production and regulation of closure. Key conceptual gaps we plan to address are what roles embryonic patterning plays in establishing the cellular and subcellular architectures that characterizes the embryo at the onset of closure and how ion fluxes contribute to closure. We will investigate the signal (or signals) that triggers the onset of closure and feedback mechanisms that compensate for genetic or physical insults to the progress of closure. We will continue to explore how force-generating cytoskeletal components are positioned, coordinated and regulated and study how adhesion complexes both transmit forces and allow cell movements. We are uniquely poised to address key extant questions that characterize the basic biology of cell sheet morphogenesis in flies. Because morphogenesis is highly conserved at the molecular, cellular and tissue levels, our work directly informs vertebrate morphogenesis in development and wound healing.