A Tfap2-mediated molecular switch for neural crest induction and specification

项目总结/摘要 神经嵴是一种多能胚胎细胞群，它构成了大部分颅面骨骼， 包括软骨、骨和结缔组织。神经嵴发育的失调导致了巨大的 大多数颅面畸形和出生缺陷。因此，揭示分子和遗传 神经嵴形成的基础对于这些疾病的诊断和治疗具有重要意义。 病理学神经嵴的形成是一个多步骤的过程。这一过程始于对 神经板边界，这是一个领域的细胞，包含前体的神经嵴，感觉基板 和中枢神经系统。随后，在指定的过程中，来自所述单元格的子集被指定。 神经板边缘开始表达真正的神经嵴细胞所特有的基因组合。 几种转录因子在神经嵴的形成过程中被粘附地使用;然而，它们如何能够 在诱导与规范期间执行不同的功能仍然不清楚。一个这样的因素，Tfap 2a，已经被 在神经嵴形成的两个步骤中都有重要作用。Tfap 2a属于Tfap 2转录本 因子家族，由旁系同源蛋白组成，可作为同源或异源二聚体调节基因 表情另外两种Tfap 2旁系同源物Tfap 2c和Tfap 2b在细胞分化的不连续阶段与Tfap 2a共表达。 神经嵴形成，在诱导和规范，分别。初步数据显示， 因子能够异源二聚化和调节不同的靶基因组。我们假设Tfap 2 异源二聚体是分子开关的一部分，以控制在诱导期间从诱导到特化的转变。 神经嵴发育首先，Tfap 2a与Tfap 2c协同介导神经板的诱导 边境第二，Tfap 2a与Tfap 2b进行异源二聚化，并驱动真正的表达。 神经嵴基因在神经板边界内的细胞亚群中。我们将通过使用 阶段特异性扰动分析和鉴定发育中蛋白质-DNA和蛋白质-蛋白质相互作用 鸟类胚胎我们的研究结果将阐明神经嵴的身份是如何逐步确定在发展过程中 并阐明了因子如何在不同的生物学背景下发挥不同的功能， 胚胎发育。

PROJECT SUMMARY/ABSTRACT The neural crest is a multipotent embryonic cell population that gives rise to most of the craniofacial skeleton, including cartilage, bone and connective tissue. Misregulation of neural crest development results in the vast majority of the craniofacial malformations and birth defects. Thus, uncovering the molecular and genetic underpinnings of neural crest formation has important implications for the diagnosis and treatment of these pathologies. Formation of the neural crest is a multistep process. This process begins with the induction of the neural plate border, which is a territory of cells that contains precursors of the neural crest, sensory placodes and central nervous system. Subsequently, during the process of specification, a subset of the cells from the neural plate border starts to express a combination of genes that is unique to bona fide neural crest cells. Several transcription factors are used reiteratively during neural crest formation; however, how they are able perform distinct functions during induction vs. specification is still unclear. One such factor, Tfap2a, has been shown to have crucial roles in both steps neural crest formation. Tfap2a belongs to the Tfap2 transcription factor family, consisting of paralogous proteins that may act as homo- or heterodimers to regulate gene expression. Two other Tfap2 paralogs, Tfap2c and Tfap2b, are co-expressed with Tfap2a at discrete stages of neural crest formation, during induction and specification, respectively. Preliminary data suggests that these factors are able to heterodimerize and regulate distinct groups of target genes. We hypothesize that Tfap2 heterodimers are part of a molecular switch to control the transition from induction to specification during neural crest development. First, Tfap2a cooperates with Tfap2c to mediate the induction of the neural plate border. Second, Tfap2a switches partners to heterodimerize with Tfap2b and drive expression of bona fide neural crest genes in a subset of cells within the neural plate border. We will test this model by employing stage-specific perturbation assays and identifying protein-DNA and protein-protein interactions in developing avian embryos. Our results will clarify how neural crest identity is progressively defined during development and shed light on how factors are able to perform distinct functions in different biological contexts throughout embryonic development.