How Gene Regulatory Networks Connect to Development

许多模型系统研究动物的早期发育，目的是了解形态发生的正常机制。这一点很重要，因为在发育早期，胚胎的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。这个复杂的序列是相当强大的，但被认为是许多无法解释的人类出生缺陷的来源。许多方法试图理解和减少这些缺陷，但从长远来看，也许最好的研究方向是彻底了解胚胎通常如何横切这些早期发育阶段。在这个项目中，目标是在一个模型系统中，海胆，了解最早的基因调控网络如何控制有助于形态发生，模式化和重新编程的细胞过程。发育的控制机制是调节所有细胞活动的转录网络。其中最好理解的基因调控网络（GRNs）是一个管理规范的早期海胆发展到原肠胚形成的开始。本项目将利用这些知识来研究如何控制开发的下一步。该想法是内中胚层GRN的子电路控制“形态调节因子”分子表达，并且这些分子反过来控制进行形态发生运动、图案化骨骼和控制胚胎中细胞重编程的能力的细胞生物学过程。将追求三个具体目标。第一个将是使用GRN，转录组，候选基因列表，和扰动，以确定控制几个阶段的原肠内陷的形态调节因子。第二个目标是研究GRN如何以精确的方式控制外胚层信号的释放，使骨骼生成细胞能够产生正确的骨骼模式。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，目标将是识别重编程的阻遏物，并记录GRN从一种规格状态转变到另一种规格状态时的状态变化。每一个目标都借鉴了对海胆基因调控网络的先进理解。

Many model systems study early development of animals with the goal to understand the normal mechanisms of morphogenesis. This is important because early in development the cells of the embryo exhibit a series of dramatic cell rearrangements that establish the primitive body plan of the 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 early developmental stages. In this project the goal is to understand in a model system, the sea urchin, how the earliest 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 activities. Among the best-understood gene regulatory networks (GRNs) is the one that governs specification 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 of the 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 perturbations to identify the morphoregulators that control the several phases of archenteron invagination. 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 correctly 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 specification state to another. Each of these aims draws upon the advanced state of understanding of the sea urchin gene regulatory network.