REGULATION OF MELANOGENESIS BY THE MOUSE AGOUTI LOCUS

小鼠 AGOUTI 基因座对黑色素生成的调节

基本信息

批准号：
3437069
负责人：
NELS H GRANHOLM
金额：
$ 6.34万
依托单位：
SOUTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-29 至 1989-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3437069
关键词：
alleles cytogenetics densitometry electron microscopy gel electrophoresis gene expression gene mutation genetic regulation isozymes melanocyte melanosomes monophenol monooxygenase morphology obesity organ culture structural genes

项目摘要

The lethal yellow gene (A-y) of the mouse agouti locus represents a valuable experimental probe to dissect cellular and molecular processes involved in the regulation of melanogenesis. A-y may impair melanogenesis via aberrant synthesis and deployment of: (1) structural proteins comprising the matrix of pigment granules and (2) tyrosinase isozymes, integral components of pigment granules which catalyze the conversion of tyrosine to melanin. Modes of A-y gene expression will be analyzed structurally by means of transmission electron microscopy of pigment granules and biochemically via characterizing the multiple molecular forms (isozymes) of tyrosinase. Comprehensive morphological characterization of the stepwise ontogeny of granules within four different genotypes of hair bulb melanocytes should reveal genuine differences in morphogenetic patterns between A-y and a alleles. The precise chronology and nature of morphological specificity should yield clues to the underlying aberrant biochemistry. Polyacrylamide gel electrophoretic analyses of tyrosinases following Alpha-MSH and glycosylation inhibitions (e.g., tunicamycin) together with the direct biochemical measurement of tyrosinase activity should allow us to assess how A-y and a differ in their ability to direct the synthesis of isozymes of tyrosinase. Data from these studies should permit us to develop a more comprehensive understanding of A-y gene and agouti locus function. This new knowledge should contribute to an overall understanding of the regulation of mammalian gene expression. Since A-y also causes obesity and diabetes, knowledge of how A-y is regulated may also be helpful in explaining the etiology of these conditions. Current work on the familial hypercholesterolemia mutation in humans documents the significance of determining the primary biochemical lesions specified by valuable mutations.

小鼠刺豚鼠基因座的致命黄色基因（A-y）代表了解剖细胞的有价值的实验探针和参与调节的分子过程黑色素生成。 A-y 可能通过异常损害黑素生成合成和部署：（1）结构蛋白包含色素颗粒基质和（2）酪氨酸酶同工酶，色素颗粒的组成部分，催化酪氨酸转化为黑色素。 A-y 基因表达模式将通过以下方式进行结构分析颜料颗粒的透射电子显微镜方法并通过表征多分子进行生物化学酪氨酸酶的形式（同工酶）。综合形态学颗粒内逐步个体发育的表征毛球黑素细胞的四种不同基因型应该揭示 A-y 和 a 之间形态发生模式的真正差异等位基因。形态学的精确年代和性质特异性应能提供潜在异常的线索生物化学。聚丙烯酰胺凝胶电泳分析 Alpha-MSH 和糖基化抑制后的酪氨酸酶（例如，衣霉素）与直接生化药物一起使用酪氨酸酶活性的测量应该使我们能够评估 A-y 和 a 指导合成的能力有何不同酪氨酸酶的同工酶。这些研究的数据应该使我们能够开发出更多全面了解A-y基因和agouti基因座功能。这些新知识应该有助于整体了解哺乳动物基因表达的调控。由于 A-y 也会导致肥胖和糖尿病，因此了解如何 A-y 受到调节也可能有助于解释病因这些条件。当前家庭工作人类高胆固醇血症突变记录了确定原发性生化病变的意义由有价值的突变指定。