Molecular Interactions during Neural Crest Formation

项目概要/摘要。 神经嵴细胞（neural crest cells，NC）是脊椎动物所特有的一种细胞，在发育早期出现，从脊椎动物的背侧迁移到脊椎动物的背侧。 神经管，并分化成大量的衍生物遍布全身，贡献神经元和神经胶质 外周神经系统、黑素细胞、颅面骨和软骨等衍生物。 失败的NC开发与大量被称为神经损伤的条件相关， 包括常见口面裂、侵袭性癌症和罕见综合征。这项研究的长期目标是 该计划是为了促进我们对负责NC形成的最早信号事件的理解。 目前，通过WNT、FGF和BMP的信号传导是被认为对细胞增殖至关重要的几个关键输入之一。 NC的形成，但我们对它们执行其作用的分子机制的理解仍然存在 有限公司为了提高我们对这一事件的认识，关键是要确定由这些途径调节的效应物 并描述其影响。本提案的目标是：1）建立和表征 第一次发现TGF β/SMAD2-SMAD3信号在NC形成的早期方面的作用， 进入神经管、迁移或分化;和2）鉴定WNT和/或TGF β的效应物， 描述其在早期NC形成过程中的作用。我们的假设是，TGF β/SMAD2-SMAD3信号转导通路可能与TGF β/SMAD2-SMAD3信号转导通路有关。 需要启动NC形成中的最早事件，并且TGFb和WNT响应性的组合 分子指导NC谱系的特异性获得。为了解决这些假设，我们的建议是指导 通过3个具体目标：1）证明TGFb/SMAD2-SMAD3信号传导的需要和贡献， 在NC形成的早期方面，2）鉴定WNT和/或TGF β的新候选效应物，并表征 它们对获得NC命运的特定贡献，和3）评估它们在脊椎动物体内的功能 胚胎这种创新的建议利用了一个强大的模型，人类数控形成的基础上， 多能干细胞和经典的鸡胚胎学，第一次解决可能的贡献， TGF β信号（而不是BMP）在这一过程中，并追求一种综合的方法来解决 WNT和TGF β的组合信号传导。该提案意义重大，因为这一领域的收益将 在命运获得和分化的关键方面的影响适用于其他细胞类型，并应提高我们的 管理与NC相关的许多病理的能力。

Project Summary/Abstract. Neural crest cells (NC) are unique to vertebrates, arise early in development, emigrate from the dorsal aspect of the neural tube, and differentiate into a plethora of derivatives throughout the body, contributing neurons and glia of the peripheral nervous system, melanocytes, and craniofacial bone and cartilage amongst other derivatives. Failed NC development is associated with a large number of conditions known as Neurocristopathies, which include common orofacial clefts, aggressive cancers and rare syndromes. The long term goal of this research program is to advance our understanding of the earliest signaling events responsible for the formation of the NC. Currently signaling by WNT, FGF and BMP are amongst a few of key inputs recognized to be critical for the formation of NC, yet our understanding of the molecular mechanisms by which they execute their effects remain limited. To improve our knowledge of this events, it is critical to identify the effectors modulated by these pathways and to characterize their effects. The objectives of this proposal are: 1) to establish and characterize for the first time the role of TGFb /SMAD2-SMAD3 signaling during early facets of NC formation, prior to their allocation into the neural tube, migration or differentiation; and 2) to identify the effectors of the WNT and/or TGFb and characterize their role during early NC formation. Our Hypotheses are that the TGFb /SMAD2-SMAD3 signaling is required to launch the earliest events in NC formation, and that a combination of TGFb and WNT responsive molecules direct the specific acquisition of the NC lineage. To address these hypotheses our proposal is guided by 3 specific aims: 1) to demonstrate the requirement and contribution of the TGFb /SMAD2-SMAD3 signaling during early facets of NC formation, 2) to identify novel candidate effectors of WNT and/or TGFb and characterize their specific contributions to the acquisition of the NC fate, and 3) to assess their function in vivo in a vertebrate embryo. This innovative proposal takes advantage of a robust model of human NC formation based in pluripotent stem cells and classic chick embryology to, for the first time address the possible contribution of TGFb signaling (not BMPs) during this process and pursues an integrative approach addressing the combinatorial signaling of WNT and TGFb. The proposal is significant because the gains in this area will have impact in key aspects of fate acquisition and differentiation applicable to other cell types, and should improve our capacity to manage the many pathologies associated with NC.