How Gene Regulatory Networks Connect to Development

许多模型系统研究动物的早期发育，目的是了解正常 形态发生的机制。这一点很重要，因为在发育早期，胚胎细胞表现出一系列戏剧性的细胞重排，建立了动物的原始身体计划。这个复杂的序列相当强大，但被认为是许多无法解释的人类先天缺陷的来源。许多方法试图了解和减少这些缺陷，但从长远来看，最好的研究方向可能是彻底了解胚胎通常如何横跨这些早期发育阶段。在这个项目中，目标是在一个模型系统--海胆中了解最早的基因调控网络如何控制有助于形态发生、模式形成和重新编程的细胞过程。发育的控制机制是调控所有细胞活动的转录网络。在最被理解的基因调控网络(GRN)中，一个控制早期海胆发育直到原肠形成开始的基因调控网络。这个项目将利用这些知识来检查下一步开发是如何控制的。这个想法是，内胚层GRN的亚回路控制着“形态调节器”分子的表达，而这些分子依次 控制进行形态发生运动的细胞生物学过程，形成骨骼图案，并控制胚胎中细胞重新编程的能力。将追求三个具体目标。第一个将是使用GRN、转录本、基因候选列表和扰动来识别 控制原肠内陷的几个阶段的形态调节器。第二个目标是研究GRN如何以一种精确的方式控制外胚层信号的释放，使骨骼形成细胞能够产生正确的图案骨骼。第三个目标将研究GRN的状态如何在重新编程时发生变化。在那里，目标将是识别重新编程的抑制因素，并记录GRN从一个特定状态转移到另一个特定状态时的状态变化。这些目标中的每一个都借鉴了对海胆基因调控网络的先进理解。

Many model systems study eariy development of animals with the goal to understand the normal mechanisms of morphogenesis. This is important because early in development the cells ofthe embryo exhibit a series of dramafic cell rearrangements that establish the primitive body plan ofthe animal. This complex sequence is quite robust yet is thought to t)e the source of many unexplained human birth defects. A number of approaches have attempted to understand and reduce those defects, but perhaps the best research direction in the long run is to thoroughly understand how embryos normally transect these eariy developmental stages. In this project the goal is to understand in a model system, the sea urchin, how the eariiest gene regulatory network controls cellular processes that contribute to morphogenesis, patterning and reprogramming. The control machinery of development are the transcriptional networks that regulate all cellular acfivifies. Among the best-understood gene regulatory networks (GRNs) is the one that governs specificafion of early sea urchin development up to the beginning of gastrulation. This project will take advantage of that knowledge to examine how the next steps of development are controlled. The idea is that sub-circuits ofthe endomesoderm GRN control "morphoregulator" molecule expression, and these in turn control the cell biological processes that conduct morphogenetic movements, pattern the skeleton, and control a capacity for cellular reprogramming in the embryo. Three specific aims will be pursued. The first will be to use the GRN, transcriptomes, gene candidate lists, and perturbafions to identify the morphoregulators that control the several phases of archenteron invaginafion. The second aim will be to examine how the GRN controls release of signals from the ectoderm in such a precise manner that enables the skeletogenic cells to produce a correcfiy patterned skeleton. The third aim will examine how the state of the GRN is able to shift as it reprograms. There the goal will be to identify a repressor of reprogramming, and also to record the state changes as the GRN shifts from one specificafion state to another. Each of these aims draws upon the advanced state of understanding of the sea urchin gene regulatory network.