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

基本信息

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
项目类别：
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

项目摘要

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（由应用提供）：小鼠外套颜色突变的位置克隆为识别和理解在生物学和疾病中起基本作用的旁分泌信号传导途径提供了基础。这种现象被称为色素型切换 - 毛囊黑色素细胞在红色/黄色菲洛南蛋白与黑色/棕色eumelanin-has的产生之间切换，对于神经内分泌，肾上腺肾上腺，外分，外在和瘦身系统所使用的途径特别有用，因为中枢性角色素的中枢性作用是素素蛋白1次获得的。化学诱变和反向遗传学方面的大规模努力逐渐使实验室小鼠作为基因发现工具的潜力逐渐饱和，但是基因组技术的进步已将正向遗传学的覆盖范围扩大到传统模型生物体之外。尽管这些途径是进化配置的，但颜色变化作为表型读数的敏感性加上观察和选择伴侣和家畜中异常突变的机会，提供了额外的机会。当前的提案着重于非模型生物中的两个“古典”外套颜色突变，在家猫中的橙色和叙利亚仓鼠的性别连接黄色（狡猾）；这些特别有趣，因为它们是X连锁的，但模仿了常染色体黑色素质素1受体（MC1R）中功能丧失的突变。我们的初步研究已经确定了橙色的候选突变和机制，以及sly的遗传图位置和位置克隆策略。关于黑色皮质素信号传导的遗传学和生物学的更多知识将来自：（1）培养细胞和转基因动物中的实验遗传研究，以实验确认和探索橙色的分子病理生理学；（2）仓鼠狡猾突变的分子鉴定和表征。