The Role of Ets1 in Melanocyte Development

描述（由申请人提供）：黑色素细胞来源于多能神经嵴（NC）细胞，其产生于神经管的背侧。虽然NC细胞最初是多能的，但它们的分化潜力逐渐受到迁移过程中遇到的内在因素和线索的限制。通过对小鼠色素突变体的研究，已经确定了几个基因参与了来自NC的黑素细胞的规范。转录因子Pax3、Sox10和Mitf的突变导致小鼠和人类的色素减退表型。最近，转录因子Ets1的缺失被证明会导致NC细胞发育不当导致心脏畸形。此外，Ets1缺失和杂合小鼠表现出腹侧色素降低，暗示该转录因子参与了NC的黑素细胞发育。Ets1是一种广泛表达的螺旋-转-螺旋转录因子，识别核苷酸序列GGAA/T。它在小鼠胚胎的各种发育器官和组织中表达，包括NC。Ets1参与多种过程，包括细胞增殖、凋亡、分化、淋巴样细胞发育、血管生成和侵袭性。提出的研究的主要目的是表征Ets1在黑素细胞发育中所起的作用。我们将(1)确定Ets1在黑素细胞谱系发育中的时间要求和作用机制。(2)确定Ets1与黑素细胞基因之间的遗传和分子相互作用。为了实现这些目标，我们将结合体内和体外增殖、细胞凋亡和迁移试验。此外，我们将进行遗传杂交、启动子分析和结合分析，以评估Ets1与Sox10、Pax3和Mitf的相互作用。我们的结果有可能揭示Ets1的新作用，并建立一个更完整的转录网络，控制黑素细胞的发育。除了与理解细胞谱系规范的基本原理相关外，我们的研究也将与理解涉及NC和皮肤色素沉着的发育障碍相关。

DESCRIPTION (provided by applicant): Melanocytes are derived from pluripotent neural crest (NC) cells, which arise from the dorsal aspect of the neural tube. Although NC cells are initially pluripotent, their differentiation potential gradually becomes restricted depending on intrinsic factors and cues they encounter during their migration. Several genes have been identified that are involved in the specification of melanocytes from the NC through the study of mouse pigmentation mutants. Mutations in the transcription factors Pax3, Sox10, and Mitf result in hypopigmentation phenotypes in mice and humans. Recently, the deletion of the transcription factor Ets1 was shown to produce cardiac malformations as a result of improper NC cell development. Furthermore, Ets1 null and heterozygous mice exhibit ventral hypopigmentation, hinting to the involvement of this transcription factor in melanocyte development from the NC. Ets1 is a widely expressed helix-turn-helix transcription factor which recognizes the nucleotide sequence GGAA/T. It is expressed in various developing organs and tissues in the mouse embryo, including the NC. Ets1 has been implicated in diverse processes, including cell proliferation, apoptosis, differentiation, lymphoid cell development, angiogenesis, and invasiveness. The main goal of the proposed study is to characterize the role played by Ets1 in melanocyte development. We will (1) Determine the temporal requirement and mechanism of action of Ets1 in the development of the melanocyte lineage. (2) Identify genetic and molecular interactions between Ets1 and melanocytic genes. To accomplish these aims we will use a combination of in vivo and in vitro proliferation, apoptosis and migration assays. Additionally, we will perform genetic crosses, promoter analysis and binding assays to evaluate the interaction of Ets1 with Sox10, Pax3, and Mitf. Our results have the potential to uncover a new role for Ets1 and establish a more complete picture of the transcriptional network that controls melanocyte development. Besides their relevance for understanding fundamental principles of cell lineage specification, our studies will also be relevant for the understanding of developmental disorders involving the NC and skin pigmentation. PUBLIC HEALTH RELEVANCE: Neural crest cells give rise to a variety of cell types and the abnormal development of these cells can result in several congenital conditions including sensorineural deafness, cranio-facial abnormalities, cardiac malformations, impaired thyroid and tongue, and pigmentation disorders. The characterization of the role played by the transcription factor Ets1 in neural crest cells and melanocytes will help further delineate the fundamental errors that underlie some of these disorders and possibly contribute to the development of targeted therapies.