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Aebp2 as an epigenetic regulator for neural crest cell

Aebp2 作为神经嵴细胞的表观遗传调节因子

基本信息

批准号：
8666770
负责人：
JOOMYEONG KIM
金额：
$ 27.86万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666770
关键词：
Adipocytes Alleles Auditory Cartilage Cells Complex Congenital Megacolon DNA-Binding Proteins Data Defect Development Drosophila genus Ectoderm Embryo Embryonic Development Endocrine system Enteric Nervous System Epigenetic Process Etiology Face Flying body movement Ganglia Gene Dosage Genes Genetic Hearing Hereditary Disease Heterozygote Hindgut Homologous Gene Homozygote Human Human Genetics Hypopigmentation Immigration Individual Insecta Knock-out Location Mammalian Cell Mammals Mediating Megacolon Molecular Mus Mutagenesis Mutant Strains Mice Mutation Neural Crest Neural Crest Cell Organ Organism Pathogenesis Pathway interactions Patients Penetrance Phenotype Play Polycomb Population Process Proteins Repression Role Series Signal Pathway Skin Spinal Ganglia Staging Testing Vertebrates Waardenburg syndrome White Spots Zinc Fingers base bone cell motility cell type disease phenotype dosage egg enhancer binding protein genome-wide human disease implantation in vivo melanocyte migration mutant public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): The neural crest cell is well known for its migration capability to various locations within the developing embryo of vertebrates. This migration is mediated through several signaling pathways. Among these pathways, mutations in the RET and EDNRB pathways often manifest as human genetic diseases, such as Hirschsprung's disease (HSCR) and Waardenburg syndrome (WS). According to our preliminary data, one evolutionarily conserved zinc finger gene, Aebp2 (Adipocyte Enhancer Binding protein 2), may play a critical role in the migration of the neural crest cell. Aebp2 previously has been identifie as a regulator controlling the migration process of the border cell in Drosophila eggs, and also as a zinc finger protein co-purified with the mammalian Polycomb Repression Complex 2 (PRC2). Consistently, our recent studies reveal that a large fraction of Aebp2's genome-wide target loci overlap with the known PcG target loci, supporting the idea that Aebp2 is likely involved in targeting the mammalian PRC2. Interestingly, Aebp2 is mainly expressed within cells of neural crest origin, such as dorsal root ganglia, and facial cartilages and bones. Furthermore, according to the results derived from a mutant mouse line disrupting Aebp2, many heterozygotes display a set of phenotypes that are usually seen in human patients with Hirschsprung's disease and Waardenburg syndrome, for example megacolon and hypopigmentation. These phenotypes suggest that Aebp2 may be required for the migration and development of the neural crest cell. Given these observations, we hypothesie that Aebp2 may be an epigenetic regulator for the neural crest cell through PcG-mediated mechanisms. In the current proposal, we will test this hypothesis with the following aims: Aim1 will further characterize the molecular basis of the phenotypes observed from the Aebp2 heterozygotes, Aim2 will test potential involvement of the PRC2-mediated mechanism in the pathogenesis of WS and HSCR, and finally Aim3 will generate a conditional KO allele of the Aebp2 locus to further delineate Aebp2 roles in neural crest cell migration. The information derived from these experiments will be helpful in unraveling the in vivo roles of Aebp2 with a special focus on its potential roles in neural crest cell migration. This information should also provide a new epigenetic-based paradigm for the pathogenesis of the human neurocristopathies, Hirschsprung's disease and Waardenburg syndrome.

描述（由申请人提供）：众所周知，神经嵴细胞具有在脊椎动物胚胎发育过程中向不同位置迁移的能力。这种迁移是通过几种信号通路介导的。在这些通路中，RET和EDNRB通路的突变常表现为人类遗传疾病，如先天性巨schsprung病（HSCR）和Waardenburg综合征（WS）。根据我们的初步数据，一个进化上保守的锌指基因Aebp2（脂肪细胞增强子结合蛋白2）可能在神经嵴细胞的迁移中起关键作用。Aebp2先前已被确定为控制果蝇卵边界细胞迁移过程的调节因子，也是与哺乳动物多梳抑制复合体2 （PRC2）共同纯化的锌指蛋白。一致地，我们最近的研究表明，Aebp2的大部分全基因组靶位点与已知的PcG靶位点重叠，支持了Aebp2可能参与靶向哺乳动物PRC2的观点。有趣的是，Aebp2主要在神经嵴起源的细胞，如背根神经节和面部软骨和骨骼中表达。此外，根据破坏Aebp2的突变小鼠系的结果，许多杂合子显示出一组通常在患有先天性巨结肠和Waardenburg综合征的人类患者中看到的表型，例如巨结肠和色素沉着减退。这些表型表明，Aebp2可能是神经嵴细胞迁移和发育所必需的。鉴于这些观察结果，我们假设Aebp2可能通过pcg介导的机制成为神经嵴细胞的表观遗传调节剂。在目前的提案中，我们将通过以下目的来验证这一假设：Aim1将进一步表征从Aebp2杂合子中观察到的表型的分子基础，Aim2将测试prc2介导的机制在WS和HSCR发病中的潜在参与，最后Aim3将产生Aebp2位点的条件KO等位基因，以进一步描述Aebp2在神经嵴细胞迁移中的作用。从这些实验中获得的信息将有助于揭示Aebp2在体内的作用，并特别关注其在神经嵴细胞迁移中的潜在作用。这一信息也应该为人类神经病变、巨结肠病和Waardenburg综合征的发病机制提供一个新的基于表观遗传学的范式。