Melanocortin signaling: genetic insight from X-linked color mutations in non-model organisms

黑皮质素信号传导：非模式生物中 X 连锁颜色突变的遗传洞察

• 批准号: 8865249
• 负责人: Gregory Stefan Barsh
• 金额: $ 32.51万
• 依托单位: HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865249
• 关键词: ART protein; Adrenal Glands; Affect; Agonist; Animal Model; Applied Genetics; Bioinformatics; Biology; Body Size; Body Weight; Chemicals; Chromosome Mapping; Code; Color; Coupled; Cultured Cells; Data; Development; Disease; Domestic Animals; Ectopic Expression; Experimental Genetics; Felis catus; Foundations; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic study; Genomics; Hair Color; Hair follicle structure; Hamsters; Health; Hormones; Human; Hydrocortisone; Individual; Knowledge; Laboratory mice; Laws; Ligands; Link; Location; Melanocortin 1 Receptor; Mesocricetus auratus; Molecular; Mus; Mutagenesis; Mutation; Names; Nature; Neurosecretory Systems; Nucleotides; Obesity; Oranges; Organism; Paracrine Communication; Pathway interactions; Phenotype; Pigments; Play; Positioning Attribute; Production; Receptor Signaling; Regulation; Regulatory Element; Role; Signal Pathway; Signal Transduction; System; Targeted Resequencing; Technology; Tissues; Transgenic Animals; Transgenic Mice; Up-Regulation; Variant; X Chromosome; agouti protein; alpha-Melanocyte stimulating hormone; companion animal; digital; eumelanin; forward genetics; gene conservation; gene discovery; genetic association; genome editing; genome sequencing; human disease; insight; interest; loss of function mutation; melanocortin receptor; melanocyte; mutant; pheomelanin; positional cloning; public health relevance; research study; reverse genetics; rho GTP-Binding Proteins; sex; skin color; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): Positional cloning of mouse coat color mutations has provided a foundation for identifying and understanding paracrine signaling pathways that play fundamental roles in biology and disease. The phenomenon known as pigment-type switching-whereby hair follicle melanocytes switch between the production of red/yellow pheomelanin vs. black/brown eumelanin-has been especially informative for pathways used by the neuroendocrine, adrenal, exocrine, and pigmentary systems because of the central role played by the Melanocortin 1 receptor. Large-scale efforts in chemical mutagenesis and reverse genetics are gradually saturating the potential of the laboratory mouse as a tool for gene discovery, but advances in genomic technology have extended the reach of forward genetics beyond traditional model organisms. Although the pathways are evolutionarily conserved, the sensitivity of color variation as a phenotypic readout coupled with the opportunity to observe and select for unusual mutations in companion and domestic animals provides additional opportunities. The current proposal focuses on two "classical" coat color mutations in non-model organisms, Orange in the domestic cat and Sex-linked yellow (Sly) in the Syrian hamster; these are especially interesting because they are X-linked, yet mimic a loss-of-function mutation in the autosomal Melanocortin 1 Receptor (Mc1r). Our preliminary studies have identified a candidate mutation and mechanism for Orange, and a genetic map position and positional cloning strategy for Sly. Additional knowledge about the genetics and biology of melanocortin signaling will come from: (1) Experimental genetic studies in cultured cells and in transgenic animals to experimentally confirm and explore the molecular pathophysiology of Orange; and (2) Molecular identification and characterization of the hamster Sly mutation.

 描述（由申请人提供）：小鼠皮毛颜色突变的定位克隆为识别和理解在生物学和疾病中发挥基本作用的旁分泌信号通路提供了基础。这种被称为色素类型转换的现象（即毛囊黑素细胞在产生红色/黄色褐黑素与黑色/棕色真黑素之间进行转换）由于黑皮质素 1 受体发挥的核心作用，对于神经内分泌、肾上腺、外分泌和色素系统使用的途径特别有帮助。化学诱变和反向遗传学方面的大规模努力正在逐渐饱和实验室小鼠作为基因发现工具的潜力，但基因组技术的进步已将正向遗传学的范围扩展到传统模式生物之外。尽管这些途径在进化上是保守的，但颜色变化作为表型读数的敏感性加上观察和选择伴侣动物和家畜中异常突变的机会提供了额外的机会。目前的提案重点关注非模式生物中的两种“经典”毛色突变，即家猫的橙色和叙利亚仓鼠的伴性黄色（Sly）；这些特别有趣，因为它们是 X 连锁的，但却模仿了常染色体黑皮质素 1 受体 (Mc1r) 的功能丧失突变。我们的初步研究已经确定了Orange的候选突变和机制，以及Sly的遗传图谱位置和定位克隆策略。关于黑皮质素信号传导的遗传学和生物学的其他知识将来自：（1）在培养细胞和转基因动物中进行实验遗传学研究，以通过实验确认和探索Orange的分子病理生理学； (2)仓鼠Sly突变的分子鉴定和表征。