Compensatory Mechanisms Regulating Neuronal Fate Following Notch Signaling Perturbation

发育中的胚胎中的一片未分化细胞产生完全运作的大脑的过程仍然是一个紧迫的科学问题，对理解大脑如何运作具有重要意义。发育中的大脑中的每个神经元都必须通过精确的空间和时间基因表达的遗传程序来采用适当的细胞身份。虽然这些遗传程序并不总是以准确的方式发挥作用，但与成人组织相比，胚胎组织具有增强的从扰动中恢复的能力。这项研究的总体目标是确定胚胎神经系统对这些偏离正常发育的反应和恢复的分子机制。这些实验将采用一种非常适合的动物模型系统，即两栖动物非洲爪蟾，它不仅表现出在发育重要的Notch信号通路的遗传干扰后进行补偿的显着能力，而且还采用了与调节早期人类神经发育的基因类似的基因。使用分子，细胞和遗传工具，这项研究将揭示特定的基因和途径，使组织从Notch信号的遗传干扰中恢复。这将拓宽我们对高度保守的Notch信号通路促进动物神经系统正常发育的方式的理解。更广泛的影响：这一知识将有助于理解人类大脑发育过程如何以及为什么会出错，以及这些遗传通路如何在新兴的再生医学领域中潜在地被操纵。 同样重要的是，这项研究将需要广泛的本科生参与的方式，融合教学和研究;一个干部的本科生，与首席研究员合作，将进行研究，作为他们的科学教育的一部分，实验也将被纳入一个新的研究为基础的基因组学课程。为了让更广泛的社区参与进来，当地教师将有机会通过夏季研讨会参与研究。

The process by which a sheet of undifferentiated cells within a developing embryo gives rise to a fully operational brain remains a pressing scientific problem with significant implications for understanding how brains function. Each neuron in the developing brain must adopt an appropriate cellular identity through a precise genetic program of spatial and temporal gene expression. Although these genetic programs do not always play out in an accurate manner, embryonic tissues have an enhanced ability to recover from perturbations as compared to adult tissues. The overall goal of this research is to identify the molecular mechanisms by which the embryonic nervous system responds to and recovers from these deviations from normal development. The experiments will employ a well-suited animal model system, namely the amphibian Xenopus laevis, that displays not only remarkable ability to compensate following genetic perturbation of the developmentally important Notch signaling pathway, but also employs a similar suite of genes to those regulating early human neural development. Using molecular, cellular and genetic tools, this research will uncover the specific genes and pathways that allow tissues to recover from genetic perturbation of Notch signaling. This will broaden our understanding of the ways in which the highly conserved Notch signaling pathway function to promote proper development of the nervous system in animals.Broader Impacts: This knowledge will contribute to understanding how and why processes go awry in human brain development and how these genetic pathways can potentially be manipulated in the emerging field of regenerative medicine. Equally importantly, the research will entail extensive undergraduate involvement in a manner that blends teaching and research; a cadre of undergraduate students, working with the principal investigator, will conduct the research as part of their science education and the experiments will also be incorporated into a new research-based genomics course. In order to engage the broader community, local teachers will have the opportunity to participate in the research through summer workshops.