CNS DEVELOPMENT AND MUTANT GENE ACTION

中枢神经系统发育和突变基因作用

• 批准号: 3407002
• 负责人: Daniel Goldowitz
• 金额: $ 12.08万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3407002
• 关键词: cell migration; central nervous system; cerebellum; congenital nervous system disorder; developmental genetics; electron microscopy; embryo /fetus cell /tissue; gene expression; genetic markers; genotype; histology; major histocompatibility complex; microscopy; mutant; radioassay; tissue mosaicism

The genetic and epigenetic mechanisms by which the brain develops into a highly ordered structure are largely unknown. The goal of this proposal is to elucidate some of the early postmitotic events in neurogenesis. There are several neurological mouse mutants which are defective in particular aspects of this developmental program. Two such genetic mutants, the weaver (wv) and the reeler (rl), hold forth fascinating information concerning the genetic control over the migratory phase of neurogenesis. These mutations affect the ability of a single cell type (the wv cerebellar granule cells) or virtually all cell types (rl) to migrate and stabilize appropriately. Experimental mouse chimeras provide a direct means to ascertain the target(s) of mutant gene action. Four cell embryos of normal (Mus caroli) and neurological mutant (Mus musculus) mice will be aggregated to form a single chimeric embryo composed of genetically normal and mutant cells. A new cell marking system will be used to identify each cell of the chimeric brain, as genotypically normal or mutant. This new cell marker, which involves the in situ hybridization of a species-specific cDNA probe to mark Mus musculus but not Mus caroli cells, will permit careful light and electron microscopic analyses of each cell's genotype compared to its phenotype. The genotype/phenotype comparisons will define the intrinsic or extrinsic nature of wv and rl mutant gene action relative to all cell types in the cerebellum. This type of information will provide a better understanding of normal brain development and how abnormal development occurs at both the more obvious (e.g., congenital ataxias) and more subtle (e.g., mental retardation) levels of dysgenesis.

大脑发育成大脑的遗传和表观遗传机制 高度有序的结构在很大程度上是未知的。 该提案的目标是 阐明神经发生中的一些早期有丝分裂后事件。 那里 有几种神经系统小鼠突变体，它们特别有缺陷 该发展计划的各个方面。 两个这样的基因突变体， 织布工 (wv) 和卷纸工 (rl)，提供令人着迷的信息 关于神经发生迁移阶段的遗传控制。 这些突变影响单个细胞类型（wv 小脑）的能力 颗粒细胞）或几乎所有细胞类型 (rl) 进行迁移和稳定 适当地。 实验性小鼠嵌合体提供了一种直接方法 确定突变基因作用的目标。 正常四细胞胚胎 （Mus caroli）和神经突变（Mus musculus）小鼠将被聚集 形成由遗传正常和突变组成的单个嵌合胚胎 细胞。 一个新的细胞标记系统将用于识别每个细胞 嵌合脑，基因型正常或突变。 这种新的细胞标记物， 其中涉及物种特异性 cDNA 探针的原位杂交 标记小家鼠而不是小家鼠细胞，将允许仔细的光线 和每个细胞的基因型与其相比的电子显微镜分析 表型。 基因型/表型比较将定义内在或 wv 和 rl 突变基因作用相对于所有细胞类型的外在性质 在小脑中。 此类信息将提供更好的 了解大脑的正常发育和异常发育如何 发生在更明显的（例如先天性共济失调）和更微妙的情况下 （例如，精神发育迟滞）发育不全的程度。