Integrating signaling and transcriptional control in neural crest specification

将信号传导和转录控制整合到神经嵴规范中

• 批准号: 9379527
• 负责人: Marcos Simoes-Costa
• 金额: $ 24.9万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379527
• 关键词: Animal Model; Binding; Biochemical; Biochemistry; Biological Assay; Bone Tissue; Cartilage; Cells; Cephalic; Chick Embryo; Chickens; Co-Immunoprecipitations; Complement; Complex; Congenital Abnormality; Connective Tissue; Craniofacial Abnormalities; DNA-Protein Interaction; Data; Defect; Development; Diagnosis; Disease; Elements; Embryo; Embryology; Employee Strikes; Enhancers; Event; Face; Fluorescence; Ganglia; Gene Activation; Gene Expression; Genes; Genetic; Genetic Transcription; Knowledge; Ligands; Light; Link; Mediating; Mediator of activation protein; Mentors; Molecular; Natural regeneration; Neural Crest; Neural Crest Cell; Nucleic Acid Regulatory Sequences; PAX7 gene; Pathway interactions; Peripheral; Phase; Play; Population; Positioning Attribute; Process; Recruitment Activity; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stem cells; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; WNT Signaling Pathway; Work; beta catenin; blastomere structure; bone; cancer cell; cell type; chromatin immunoprecipitation; craniofacial; craniofacial development; experimental study; insight; knock-down; loss of function; melanocyte; member; nano-string; neural plate; novel; novel marker; overexpression; progenitor; programs; public health relevance; receptor; regenerative; regenerative therapy; repaired; skeletal; stem; stem cell differentiation; transcription factor; transcriptome

DESCRIPTION (provided by applicant): The neural crest is a multipotent embryonic cell population that plays a central role in craniofacial development, giving rise to most of the skeletal elements of the face. Abnormal neural crest development is the leading cause of craniofacial malformations and birth defects. Specification of the cranial neural crest is a complex process that requires interplay between signaling molecules, receptors, and transcriptional regulators. In particular, the Wnt signaling pathway has been shown to be a major driver of neural crest development. Data obtained from different model organisms show that inhibition of Wnt activity abrogates expression of neural crest genes, while overactivation of canonical Wnt pathway components results in expansion of neural crest fates. However, the molecular mechanism through which Wnt signaling elicits neural crest identity remains elusive. In this application, I will investigate how the Wnt-pathway drives activation of the genes that endow the neural crest with its unique features. I hypothesize that Wnt-effector genes cooperate with transcriptional regulators present in progenitors to trigger the neural crest specification program. This hypothesis is supported by my preliminary experiments, which suggests that transcriptional regulator Axud1 acts as a previously unidentified link between Wnt signaling and neural crest specification. Here, I will determine the role of Axud1 in specification by using loss of function approaches in the chicken embryo, and scrutinize how it is activated by Wnts in neural crest progenitors. Subsequently, I will investigate how members of the Wnt pathway interact with other drivers of neural crest specification to activate the expression of downstream targets at the cis-regulatory level. The results of the proposed experiments will shed light on how signaling pathways are integrated with the transcriptional machinery to allow for the emergence of nascent neural crest cells. Expanding the knowledge of molecular programs controlling the development of the cephalic neural crest will yield novel insights into the genetic basis of craniofacial disease and can impact therapeutic and regenerative applications.

描述(申请人提供)：神经脊是一个多潜能的胚胎细胞群体，在头面部的发育中发挥核心作用，产生面部的大部分骨骼元素。神经脊发育异常是导致颅面畸形和出生缺陷的主要原因。颅神经脊的规范是一个复杂的过程，需要信号分子、受体和转录调控因子之间的相互作用。特别是，Wnt信号通路已被证明是神经脊发育的主要驱动力。来自不同模式生物的数据表明，抑制Wnt活性会取消神经脊基因的表达，而过度激活 规范的Wnt通路成分导致神经脊命运的扩张。然而，Wnt信号引起神经峰同一性的分子机制仍然不清楚。在这项应用中，我将研究Wnt通路如何驱动赋予神经脊独特功能的基因的激活。我推测，Wnt效应基因与祖细胞中存在的转录调节因子合作，触发了神经脊规范程序。这一假设得到了我的初步实验的支持，该实验表明转录调控因子Axud1在Wnt信号和神经峰规范之间起到了以前未被识别的联系。在这里，我将使用Loss来确定Axud1在规范中的角色 在鸡胚胎中的功能途径，并仔细研究它是如何在神经脊祖细胞中被WNT激活的。随后，我将研究Wnt通路的成员如何与其他神经脊规范的驱动因素相互作用，在顺式调控水平上激活下游靶标的表达。拟议的实验结果将阐明信号通路如何与转录机制整合，以允许新生神经脊细胞的出现。扩展控制头神经脊发育的分子程序的知识将产生对遗传学的新见解 这是头面部疾病的基础，并可能影响治疗和再生应用。