EMBRYOLOGIC CONSEQUENCES OF TRISOMY 16 IN MICE

16 三体对小鼠的胚胎学影响

• 批准号: 3317599
• 负责人: Mary L Oster-Granite
• 金额: $ 14.99万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3317599
• 关键词: RNase protection assay; acetylcholine; acetylcholinesterase; body weight; brain; choline acetyltransferase; developmental genetics; developmental neurobiology; electron microscopy; embryo /fetus tissue /cell culture; gender difference; gene expression; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; light microscopy; mutant; neurochemistry; neurogenesis; northern blottings; phenotype; polymerase chain reaction; postnatal growth disorder; radioimmunoassay; somatostatin; spinal cord; trisomy

The long term objective of this research program remains the analysis of the developmental consequences of overexpression of genes triplicated in the trisomy 16 (Ts16) mouse. Two such genes located on mouse chromosome 16 (MMU 16) encode preprosomatostatin (Smst) and a transcription factor, pit-1 (dwarf, dw). Although dwarf and Smst are not the same gene, dwarf mice express elevated levels of preprosomatostatin in various regions of their brains, and have premature loss of Smst expressing cells in regions of their hypothalami. The overall aims of this proposal are to determine whether the products of the Smst gene function to modulate growth and/or development and survival of neurons and glia in the early nervous system in normal, Ts16, and dwarf mice and thus to contribute to the structural and neurochemical deficits observed in Ts16 mice and dwarf mice. to dissect the neurobiological effects of excess somatostatin expression independent of the effects that arise from triplication of the dwarf locus in Ts16 mice, mice transgenic for the endogenous Smst gene will also be studied. Five separate lines of such Smst transgenic (SmstTg) mice have been developed, and differ in genetic background, levels of overexpression, and phenotype. Three of these SmstTg lines have been well characterized and exhibit both intrauterine and postnatal growth alterations and variable levels of overexpression of Smst in different regions of their brains. One line, SmstTg13, exhibits intrauterine and postnatal growth retardation, excess Smst expression, increased levels of proSRIF derived peptides, and cholinergic deficits, reminiscent of the phenotype of the dwarf mouse. The first specific aim is to characterize Smst expression in early brain development in normal, Ts16, Smst transgenic, and dwarf mice, and to correlate such expression with parameters of growth during the prenatal and postnatal period. The second specific aim is to examine the generation and survival of cholinergic neuron populations in the brain and spinal cord of these groups of mice relative to levels of Smst expression. The third specific aim is to analyze particular behavioral and neurochemical changes which occur in normal, SmstTg, and dwarf mice during the postnatal period, particularly changes which occur in spontaneous activity and in the parameters of the cholinergic system. Methods for RNA and DNA analysis and quantification, polymerase chain reaction and reverse transcription polymerase chain reaction, in situ hybridization, radioimmunoassay, immunocytochemistry, single pulse and cumulative cell birthdating, and light and electron microscopy will be used in these studies. Together, these studies will help us to obtain a greater understanding of the role of somatostatin in normal and abnormal development of the nervous system and the relationship between smst expression and the expression of the transcription factor, pit-1.

该研究计划的长期目标仍然是对 基因过表达的发展后果一式三份 三体菌16（TS16）小鼠。 两个位于小鼠染色体上的基因 16（MMU 16）编码前瘤蛋白（SMST）和转录因子， PIT-1（矮人，DW）。 尽管矮人和SMST不是同一基因，但矮人 小鼠在各个区域的prodosomatatin表达升高的水平 他们的大脑，并过早地损失SMST在区域中表达细胞 他们的下丘脑。 该提议的总体目的是确定 SMST基因的产物是否功能调节生长和/或 早期神经系统中神经元和神经胶质的发展和生存 在正常情况下，TS16和矮小鼠，因此有助于结构 在TS16小鼠和矮小鼠中观察到的神经化学缺陷。 到 剖析过度生长抑素表达的神经生物学作用 独立于矮人的三重效应产生的效果 TS16小鼠中的基因座，内源性SMST基因的小鼠转基因将 也可以研究。 这种SMST转基因（SMSTTG）的五行 已经开发了小鼠，并且遗传背景有所不同，水平 过表达和表型。 这些SMSTTG系列中的三个已经 表征良好，表现出宫内和产后生长 SMST的变化和可变水平 他们大脑的区域。 一条线SMSTTG13，表现出宫内和 产后生长迟缓，过度SMST表达，水平增加 prof衍生的肽和胆碱能缺陷的含量，让人联想到 矮小鼠的表型。 第一个具体目的是表征早期大脑中的SMST表达 正常，TS16，SMST转基因和矮小小鼠的发育，以及 将这种表达与产前期间的生长参数相关 和产后期。 第二个具体目的是检查 大脑中胆碱能神经元种群的产生和存活 这些小鼠相对于SMST水平的脊髓和脊髓 表达。 第三个具体目的是分析特定的行为 和神经化学的变化发生在正常，SMSTTG和矮小小鼠中 在产后，特别是发生的变化 自发活动和胆碱能系统的参数。 RNA和DNA分析和定量，聚合酶链的方法 反应和逆转录聚合酶链反应，原位 杂交，放射免疫测定，免疫细胞化学，单脉冲和 累积细胞生育，光和电子显微镜将是 这些研究用于这些研究。 这些研究一起将帮助我们获得 对生长抑素在正常和 神经系统的异常发展和 SMST表达和转录因子的表达，PIT-1。