GENETIC CONTROL OF MONAMINERGIC AXON GROWTH

单胺能轴突生长的遗传控制

• 批准号: 3400444
• 负责人: PAT LEVITT
• 金额: $ 12.77万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3400444
• 关键词: affinity labeling; axon; biological models; gene mutation; genetic regulation; genotype; hippocampus; histochemistry /cytochemistry; immunochemistry; locus coeruleus; major histocompatibility complex; nervous system transplantation; neural information processing; neuroanatomy; neurochemistry; neurofilament; sympathetic nervous system; tissue mosaicism; visceral afferent nerve

The proposed experiments will investigate the genetic and environmental mechanisms that affect normal axon growth in the developing mammalian nervous system. We will test 3 basic hypotheses: 1) Genes intrinsic to a neuron can control axon growth, 2) Genes regulate the responsiveness of neurons to extrinsic cues that modulate axon growth and 3) Gene defects that alter axon growth result in specific compensatory changes in normal parts of the system. A model system, based on a single locus gene mutation, will be used: The locus coeruleus (LC) noradrenergic neurons in the homozygous mutant mouse tottering (tg/tg) are a defined group of nerve cells whose exuberant axon growth in target areas is caused by a single locus gene mutation. We will transplant in oculo fetal LC neurons from tg/tg and normal (+/+) mice to determine whether the gene mutation altering axon growth affects directly an intrinsic developmental regulatory mechanisms in LC neurons. The intrinsic nature of the gene defect will also be assessed in tg/tg +/+ chimeras, using double labeling methods that combine in situ hybridization or enzyme histochemistry and immunocytochemistry to identify simultaneously genotype and phenotype. We will determine whether the single locus gene mutation has altered the ability of LC neurons to respond to environmental cues provided by targets or other fiber systems that normally contribute to the regulation of axon growth by the use of double (LC and target) and triple (LC, target and another fiber system) transplantation paradigms. The compensatory responses of LC afferents to the abnormal axon proliferation will be investigated using quantitative morphometric ultrastructural analysis. The relative contribution of the gene in influencing axongenesis will be observed by combining in a unique fashion different experiment systems. These studies may provide rational strategies for analyzing fiber growth abnormalities in development or following injury.

拟议的实验将调查遗传和环境 影响发育中哺乳动物正常轴突生长的机制 神经系统 我们将测试3个基本假设：1）基因内在的一个 神经元可以控制轴突的生长，2）基因调节神经元的反应性。 神经元对调节轴突生长的外部线索的反应; 3）基因缺陷 改变轴突生长导致特定的正常的代偿性变化， 系统的一部分。 一个模型系统，基于一个单位点基因 突变，将使用：蓝斑（LC）去甲肾上腺素能神经元， 纯合子突变小鼠蹒跚（tg/tg）是一组确定神经 细胞，其在靶区域的旺盛轴突生长是由单个 位点基因突变。 我们将移植眼内胎儿LC神经元， tg/tg和正常（+/+）小鼠，以确定基因突变是否改变 轴突生长直接影响一种内在的发育调节机制， LC神经元中的机制。 基因缺陷的内在本质将 也可以在tg/tg +/+嵌合体中进行评估，使用双标记方法， 联合收割机原位杂交或酶组织化学， 免疫细胞化学同时鉴定基因型和表型。 我们 将确定单位点基因突变是否改变了 LC神经元对目标提供的环境线索作出反应的能力 或其他通常有助于轴突调节的纤维系统 通过使用双重（LC和目标）和三重（LC，目标和 另一种纤维系统）移植范例。 补偿 LC传入神经对异常轴突增殖的反应将是 使用定量形态学超微结构分析进行研究。 的 该基因在影响轴突发生中的相对贡献将是 通过以独特的方式组合不同的实验系统来观察。 这些研究可为分析纤维生长提供合理的策略 发育异常或受伤后的异常。