The Role of Ets1 in Melanocyte Development

Ets1 在黑素细胞发育中的作用

• 批准号: 8232742
• 负责人: LIDIA KOS
• 金额: $ 37.73万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232742
• 关键词: Address; Antibodies; Apoptosis; Base Sequence; Binding; Binding Sites; Biological Assay; Cell Lineage; Cell Proliferation; Cells; Color; Congenital Heart Defects; Congenital Megacolon; Cues; Defect; Development; Developmental Process; Disease; Dorsal; Embryo; Embryonic Development; Exhibits; Face; Galactosidase; Genes; Genetic; Genetic Crosses; Goals; Hair; Helix-Turn-Helix Motifs; Human; Hypopigmentation; In Situ Hybridization; In Vitro; Intrinsic factor; Label; LacZ Genes; Lead; Lymphoid Cell; Melanins; Migration Assay; Mus; Mutation; Neural Crest; Neural Crest Cell; Neural tube; Neurocutaneous Syndromes; Organ; Pattern; Phenotype; Piebaldism; Pigmentation Disorders; Pigmentation physiologic function; Pigments; Play; Positioning Attribute; Process; Production; Role; Sensorineural Hearing Loss; Signaling Pathway Gene; Site; Skin; Skin Pigmentation; Staining method; Stains; Sturge-Weber Syndrome; Thyroid Gland; Tietze' s Syndrome; Time; Tissues; Tongue; Transcriptional Regulation; Transgenic Mice; Ultraviolet Rays; Waardenburg syndrome; angiogenesis; cell type; chromatin immunoprecipitation; craniofacial; developmental disease; in vivo; malformation; melanoblast; melanocyte; melanoma; migration; mutant; promoter; transcription factor

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.

描述（由申请人提供）：黑素细胞来源于多能神经嵴（NC）细胞，其产生于神经管的背面。虽然NC细胞最初是多能的，但其分化潜力逐渐受到限制，这取决于它们在迁移过程中遇到的内在因素和线索。通过对小鼠色素沉着突变体的研究，已经鉴定出几个基因参与NC黑素细胞的特化。转录因子Pax 3、Sox 10和Mitf的突变导致小鼠和人类色素减退表型。最近，转录因子Ets 1的缺失被证明会导致NC细胞发育不良而导致心脏畸形。此外，Ets 1无效和杂合子小鼠表现出腹侧色素减退，暗示该转录因子参与NC的黑素细胞发育。Ets 1是广泛表达的螺旋-转角-螺旋转录因子，其识别核苷酸序列GGAA/T。它在小鼠胚胎的各种发育器官和组织中表达，包括NC。Ets 1参与多种过程，包括细胞增殖、凋亡、分化、淋巴样细胞发育、血管生成和侵袭。这项研究的主要目标是描述Ets 1在黑素细胞发育中所起的作用。我们将（1）确定Ets 1在黑素细胞谱系发育中的时间要求和作用机制。(2)确定Ets 1和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，我们将使用体内和体外增殖、凋亡和迁移测定的组合。此外，我们将进行遗传杂交，启动子分析和结合试验，以评估Ets 1与Sox 10，Pax 3和Mitf的相互作用。我们的研究结果有可能揭示Ets 1的新作用，并建立一个更完整的控制黑素细胞发育的转录网络。除了与理解细胞谱系特化的基本原理相关外，我们的研究还与理解涉及NC和皮肤色素沉着的发育障碍相关。 公共卫生关系：神经嵴细胞产生多种细胞类型，这些细胞的异常发育可导致几种先天性疾病，包括感音神经性耳聋、颅面畸形、心脏畸形、甲状腺和舌受损以及色素沉着疾病。转录因子Ets 1在神经嵴细胞和黑素细胞中所起作用的表征将有助于进一步阐明这些疾病的基本错误，并可能有助于靶向治疗的发展。