Functional Roles of Wnt and Snail2 Target Genes in Neural Crest Development

描述（由申请人提供）：候选人研究生涯的总体主题是确定Wnt信号通路激活靶基因表达并随后以上下文依赖和时间方式影响特定细胞类型产生的分子基础。Wnt信号通路及其组分在胚胎发育和正常细胞向癌细胞转化的成熟组织中反复使用，证明了该通路的重要性。Wnt信号在神经嵴的发育中起着重要作用，神经嵴是一群帮助胚胎定型的迁移细胞。由于其对胚胎结构的贡献，神经嵴发育缺陷引起多种综合征、疾病和癌症，包括Axenfeld-Rieger综合征、DiGeorge综合征和tter - collins综合征以及神经纤维瘤病。为了进一步了解Wnt信号如何调节神经嵴发育，候选人进行了筛选，以确定参与该过程的Wnt信号的新靶点。此外，对已知Wnt靶基因（如Snail2 (Slug)）的作用的研究使她能够阐明Snail2如何在神经嵴发育的背景下调节其分子靶标的表达。胚胎学和生化方法将用于确定这些靶点的功能意义及其受Wnt调控的模式。总的来说，这些方法将为她提供一组候选分子，这些分子可能在神经嵴衍生结构的产生中起作用，如颅面骨骼和周围神经系统，以及为神经嵴衍生癌症的发展提供见解。综上所述，候选人的长期研究和职业目标包括进行指导研究（在她博士后培训的最后几年）和独立研究（作为首席研究员），以阐明神经嵴发育过程中Wnt信号传导的分子机制，并将这些知识应用于整个人类发展。这项研究与公共卫生有关，因为神经嵴对人体的正常形成具有生物学意义，例如面部骨骼、神经和皮肤色素细胞。神经嵴细胞如何正确地形成如此多样的结构，可以帮助我们理解当神经嵴发育受损、人类综合症和癌症出现时发生了什么。

DESCRIPTION (provided by applicant): The general theme of the candidate's research career has been to determine the molecular basis by which the Wnt signaling pathway activates expression of target genes and subsequently affects the generation of a particular cell type, in a context-dependent and temporal manner. The Wnt signaling pathway and its components are used reiteratively throughout embryonic development and in mature tissues during the transformation of normal cells to cancerous ones, demonstrating the importance of this pathway. Wnt signaling plays a significant role in the development of the neural crest, a population of migratory cells that helps pattern the embryo. Because of its contribution to embryonic structures, defects in neural crest development give rise to multiple syndromes, diseases, and cancers, including Axenfeld-Rieger, DiGeorge, and Treacher-Collins syndromes, and neurofibromatosis. To further understand how Wnt signaling regulates neural crest development, the candidate has performed a screen to identify novel targets of Wnt signaling involved in this process. Furthermore, investigation into the role of known Wnt target genes, such as Snail2 (Slug) allows her to elucidate how Snail2 regulates expression of its molecular targets in the context of neural crest development. Embryological and biochemical methods will be employed to determine the functional significance of these targets and their mode of regulation by Wnt. Overall, these approaches will provide her with a group of candidate molecules that will likely function in the generation of structures derived from the neural crest, such as the craniofacial skeleton and peripheral nervous system, as well as provide insight into the development of neural crest-derived cancers. In summary, the candidate's long-term research and career objectives include conducting mentored research (in the final years of her postdoctoral training) and independent research (as a principal investigator) to elucidate the molecular mechanism underlying Wnt signaling during the development of the neural crest, and applying this knowledge to human development as a whole. This research is relevant to public health because of the biological significance of the neural crest to the proper formation of human bodies, such as the bones of the face, nerves, and skin pigment cells. How neural crest cells properly become such diverse structures can help us comprehend what happens when neural crest development is impaired, and human syndromes and cancers arise.