GENETIC STRAIN EFFECTS AND DOPAMINE CELL LOSS IN WEAVER MUTANT

Weaver 突变体中的遗传应变效应和多巴胺细胞损失

• 批准号: 6112327
• 负责人: BERNARDINO Francesco GHETTI
• 金额: --
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112327
• 关键词: 3,4 dihydroxyphenylacetate; alleles; animal breeding; cell death; corpus striatum; developmental neurobiology; disease /disorder model; dopamine; dopamine receptor; gene mutation; genetic strain; genotype; histology; homovanillate; homozygote; immunocytochemistry; inbreeding; laboratory mouse; mesencephalon; mutant; neural degeneration; neurogenetics; neurons; phenotype; statistics /biometry; tyrosine 3 monooxygenase

Knowledge of the mechanisms controlling nerve cell number and nerve cell loss in the brain is central to the understanding of central nervous system functions in health and disease. The evidence of differences in nerve cell number within brain regions among different strains of mice indicates that putative genes control the variability of neuronal number in discrete areas of the brain. In mice of the CBA/J strain the number of midbrain dopamine (DA) neurons in some 20% lower than in BALB/cJ mice. It is conceivable that the number of midbrain DA neurons is genetically regulated also in man. If certain individuals be endowed with a lesser number of a specific nerve cell population, say the DA cell population, would such individuals, as a result of a mutant gene, fall victim to functional deficit - Parkinson Disease - earlier? Is there a threshold? We have previously found that the single gene mutation weaver (wv) affects the viability of the midbrain DA neurons and induces a postnatal loss of these cells. In hybrid B6CBA- Aw-j/A mice, homozygous for the wv gene, the neurons of the mesotelencephalic DA system are approximately 47% fewer than in the wild type by 90 days of age. The influence of the strain-associated variability of the number of midbrain DA neurons upon the phenotypic expression of a single gene mutation affecting that neuronal population, has not been previously investigated. We intend to determine whether the percentage of DA neurons lost postnatally as an effect of the wv gene is fixed, regardless of strain, or varies in relation to the number of DA neurons with which the specific strain is originally endowed. To this end we will obtain homozygous wv mutant mice congenic in the CBA/J strain as well as in the BALB/cJ strain, will determine the number of neurons of the mesencephalic DA system in wv homozygotes and controls at maturity for each strain and will measure neurochemical dopaminergic markers in the midbrain and the striatum of mutant and wild type mice. The wv gene will be introduced in the BALB/cJ and CBA/J background using the breeding technique known as the backcross system. Thirteen backcross generations will be required to produce the congenic lines. When these will be obtained, nerve cell counts and statistical analysis of DA neurons will be carried out in the midbrain. The data will allow us to determine whether there is a relation between the strain-specific nerve cell number and the number of cells that are programmed to die as a consequence of a single gene mutation. With these studies it may be possible to extrapolate general neurobiological principles and to formulate new hypotheses to be tested studying degenerative diseases of the human brain, such as Parkinson disease.

了解神经细胞数量和神经细胞数量的控制机制 大脑中的损失是理解中枢神经系统的核心 在健康和疾病中发挥作用。 神经细胞差异的证据 不同品系小鼠大脑区域内的数量表明， 推定的基因控制离散区域神经元数量的变异性 大脑。 在CBA/J品系小鼠中，中脑多巴胺的数量 (DA)神经元比BALB/cJ小鼠低约20%。 可以想象 中脑DA神经元的数量也受到基因调控， 伙计 如果某些个体被赋予较少数量的特定 神经细胞群，比如DA细胞群，会不会这样的个体， 由于突变基因，成为功能缺陷的受害者-帕金森 疾病-早些时候？ 有门槛吗？ 我们先前发现， 单基因突变韦弗（wv）影响中脑的活力 DA神经元，并诱导这些细胞的出生后损失。 在混合动力B6 CBA中- Aw-j/A小鼠，wv基因纯合子， 中端脑DA系统比野生动物少约47 90天的年龄。 应变相关变异性的影响 中脑DA能神经元数量的表型表达后， 影响神经元群体单个基因突变， 以前调查过。 我们打算确定， 由于wv基因的作用固定，出生后DA神经元丢失， 无论应变如何，或与DA神经元的数量有关 这是特定菌株最初被赋予的。 为此，我们将 获得与CBA/J品系同源的纯合wv突变小鼠， BALB/cJ株，将决定神经元的数量， 成年时wv纯合子和对照组中脑DA系统 并将测量中脑的神经化学多巴胺能标记物 以及突变型和野生型小鼠的纹状体。 wv基因将是 在BALB/cJ和CBA/J背景下使用育种技术引入 称为回交系统。 十三个回交世代将是 产生同类系所必需的。 当这些将获得，神经 细胞计数和DA神经元的统计分析将在 中脑 这些数据将使我们能够确定是否存在 应变特异性神经细胞数与神经细胞数量之间的关系 一个基因导致细胞死亡 突变 有了这些研究，就有可能推断出 神经生物学原理，并制定新的假设进行测试 研究人类大脑的退化性疾病，如帕金森病， 疾病