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Identifying Sox family transcription factor partners and targets essential for neural crest formation

识别 Sox 家族转录因子伙伴和神经嵴形成所必需的靶标

基本信息

批准号：
10229492
负责人：
Elizabeth (Betsy) Schock
金额：
$ 7.19万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229492
关键词：
Affect Body Regions Cells ChIP-seq Chimeric Proteins Chondrocytes Coupled Craniofacial Abnormalities Data Data Set Defect Development Disease Ectoderm Embryo Embryonic Development Etiology Evolution Family Gene Expression Genes Genetic Transcription Germ Layers Grant Individual Investigation Lead Light Maintenance Mass Spectrum Analysis Mediating Mesoderm Molecular Mutation Neural Crest Neural Crest Cell Neuroglia Patients Play Pluripotent Stem Cells Population Property Protein Microchips Regulation Regulator Genes Role Specificity Syndrome Techniques Tertiary Protein Structure Tissues Validation Vertebrates Work blastocyst blastomere structure cell type craniofacial complex embryo cell embryonic stem cell experimental study in vivo insight loss of function malformation neurodevelopment novel overexpression pluripotency pluripotency factor stem stem cell population stem cells stem-like cell transcription factor

项目摘要

Project Summary/Abstract Neurocristopathies are a class of syndromes that are predominately characterized by malformations in the craniofacial complex. These defects are caused by aberrant development of the neural crest (NC), a stem cell population unique to vertebrates. As a means of better understanding the molecular basis for neurocristopathies, a thorough investigation of the various aspects of NC cell development is necessary. One unique property of the NC is their broad developmental potential which grants them the ability to give rise to cell types typically attributed to multiple germ layers (mesoderm and ectoderm). Previous work from my lab has lead to the genesis of the hypothesis that the expanded embryonic potential of the NC can be attributed to the retention of stem cell-like pluripotency in these cells. Still a major unanswered question is how NC cells retain their stem cell-like potential even as neighboring cells undergo lineage restriction. Transcription factors often direct cell fate decisions or maintain cell states. In this proposal, I investigate how Sox transcription factors may regulate NC formation and their ability to maintain a stem cell-like state. SoxB1 factors, a subfamily of Sox transcription factors, are expressed in early pluripotent cells of the embryo (blastula) and help to positively regulate pluripotency in that tissue. In contrast, SoxE factors are absent from the blastula, but are robustly expressed in the NC. Effectively, there is switch in the subfamily of Sox factors that is utilized in two temporally distinct stem cell populations in the embryo. Recent work from my lab has shown that this transition from SoxB1 to SoxE factors is essential for NC formation; however, we have yet to define the mechanisms by which SoxE factors help to promote the formation of NC stem cells. In this proposal, I plan to utilize techniques such as IP-mass spectrometry and ChIP-seq to identify potential transcriptional partners and targets of Sox factors that are required for NC formation and controlling pluripotency in the blastula. Using these datasets and further experimental validation of Sox partner and target candidates, I will identify key similarities and differences between the SoxE and SoxB1 partners and targets in these stem cell populations. This will enhance our understanding of the molecular underpinnings of NC formation and maintenance of stem cell potential. Furthermore, these data will help us to understand why the formation of the NC was accompanied by a switch in the utilization of Sox factor subfamilies. !

项目总结/摘要神经损伤是一类综合征，其主要特征是脑内畸形。颅面复合体这些缺陷是由神经嵴（NC）的异常发育引起的，脊椎动物特有的种群。为了更好地理解为了研究神经细胞学，有必要对NC细胞发育的各个方面进行彻底的研究。一 NC的独特属性是其广泛的发展潜力，赠款其能够产生典型地归因于多个胚层（中胚层和外胚层）的细胞类型。我实验室以前的工作这导致了一种假说的产生，即NC的胚胎潜能的扩大可以归因于在这些细胞中保持干细胞样多能性。仍然有一个主要的未回答的问题是NC细胞如何保留它们的干细胞样潜能，即使邻近细胞经历谱系限制。转录因子通常指导细胞命运决定或维持细胞状态。在这个建议中，我调查如何Sox转录因子可能调节NC形成和维持干细胞样状态的能力。SoxB 1因子，Sox的一个亚家族转录因子，在胚胎（囊胚）的早期多能细胞中表达，并有助于调节该组织中的多能性。相比之下，SoxE因子在囊胚中不存在，但在囊胚中强烈表达。在NC中表示。有效地，在两个时间上利用的Sox因子的子家族中存在切换。胚胎中不同的干细胞群。我的实验室最近的工作表明， SoxB 1到SoxE因子对于NC的形成是必不可少的;然而，我们还没有确定其机制， SoxE因子有助于促进NC干细胞的形成。在这个建议中，我计划利用技术，作为IP-质谱和ChIP-seq来鉴定Sox因子的潜在转录伴侣和靶标这是NC形成和控制囊胚中多能性所需的。使用这些数据集和进一步 Sox合作伙伴和目标候选人的实验验证，我将确定关键的相似性和差异 SoxE和SoxB 1伴侣和靶点之间的关系。这将提高我们的了解NC形成和维持干细胞潜能的分子基础。此外，这些数据将帮助我们理解为什么NC的形成伴随着开关在利用Sox因子亚家族方面。 !