Aebp2 as an epigenetic regulator for neural crest cell

描述（由申请人提供）：众所周知，神经嵴细胞具有迁移到脊椎动物发育胚胎内不同位置的能力。这种迁移是通过几个信号通路介导的。在这些途径中，RET和EDNRB途径中的突变通常表现为人类遗传性疾病，如先天性巨结肠症（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，Aebp 2（脂肪细胞增强结合蛋白2），可能在神经嵴细胞的迁移中发挥关键作用。Aebp2以前已被鉴定为控制果蝇卵中边缘细胞的迁移过程的调节剂，并且还被鉴定为与哺乳动物多梳抑制复合物2（PRC2）共纯化的锌指蛋白。一致地，我们最近的研究表明，Aebp 2的全基因组靶基因座的很大一部分与已知的PcG靶基因座重叠，支持Aebp 2可能参与靶向哺乳动物PRC 2的观点。有趣的是，Aebp2主要在神经嵴起源的细胞中表达，如背根神经节、面部软骨和骨骼。此外，根据来自破坏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病和Waardenburg综合征的人类患者中观察到的表型，例如巨结肠和色素减退。这些表型表明，Aebp2可能需要的迁移和神经嵴细胞的发展。鉴于这些观察结果，我们假设Aebp2可能是通过PcG介导机制的神经嵴细胞的表观遗传调节因子。在目前的提案中，我们将测试这一假设与以下目标：Aim1将进一步表征从Aebp2杂合子观察到的表型的分子基础，Aim2将测试潜在的参与PRC2介导的机制在WS和HSCR的发病机制，最后Aim3将产生一个条件KO等位基因的Aebp2基因座，以进一步描绘Aebp2在神经嵴细胞迁移的作用。从这些实验中获得的信息将有助于解开Aebp2在体内的作用，特别关注其在神经嵴细胞迁移中的潜在作用。这一信息也将为人类神经损伤、先天性巨结肠和Waardenburg综合征的发病机制提供一个新的基于表观遗传学的范例。

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.