ANATOMY OF REGULATORY GENES IN FOREBRAIN DEVELOPMENT

研究建议：皮质发育取决于一系列细胞 涉及生长因子和神经递质的相互作用。在成人中 大脑，这些分子诱导快速和瞬时的表达 可能控制长期反应的蛋白质。类比小说 调节基因，由突触活动诱导并在高水平表达 在发育中的皮质中，在关键时期的水平被确定在Dr。 沃利的实验室通过分子克隆技术。ADR-1编码45 与血影蛋白同源的KD蛋白，似乎是大脑特有的 并在出生后的关键时期表现出来，这表明 细胞外刺激和神经元形态变化之间的关系。Rasp 编码一种与ras(40%同源性)和rap同源的GTP结合蛋白。 (45%同源性)，并在胎鼠大脑皮质表达。就像RAS一样， Rasp转化NIH3T3细胞，表明在细胞内发挥积极作用 发信号。 中心假说是生理活动导致 ADR-1和rasp的表达及其细胞内调控 本地化。这将在正常大鼠皮质中进行测试，在AIMS 1和 2.在获得这个基本框架后，一项类似的研究 将在两个动物模型中执行，其特点是 皮质输入，与精神发育迟缓相关：大鼠 营养环境剥夺与基底前脑小鼠 新生儿损害(目标3和4)。 环境：考夫曼博士的活动将在 智障中心，由几个研究小组组成 研究与精神发育迟滞有关的不同方面 比如大脑发育过程中的基因表达。

Research proposal: Cortical development depends on a sequence of cellular interactions involving growth factors and neurotransmitters. In adult brain, these molecules induce the rapid and transient expression of proteins that may control long-term responses. Analogous novel regulatory genes, induced by synaptic activity and expressed at high levels, at critical periods, in developing cortex were identified in Dr. Worley's laboratory by molecular cloning techniques. Adr-1 encodes a 45 kD protein with homology to spectrin, that appears to be brain specific and expressed during the critical postnatal period, suggesting a link between extracellular stimuli and changes in neuronal morphology. Rasp encodes a GTP-binding protein with homology to ras (40% identity) and rap (45% identity) and is expressed in the prenatal rat cortex. Like ras, rasp transforms NIH3T3 cells, indicating an active role in cellular signalling. The central hypothesis is that physiological activity induces the expression of both adr-1 and rasp and also modulates their intracellular localization. This will be tested, in normal rat cortex, in Aims 1 and 2, respectively. After obtaining this basic framework, a similar study will be performed in two animal models, characterized by decreased cortical input, and relevant for mental retardation: rats with nutritional-environmental deprivation and mice with basal forebrain neonatal lesions (Aims 3 and 4). Environment: Dr. Kaufmann's activities will be in the context of the Mental Retardation Center, which comprises several research groups studying different aspects of development relevant to mental retardation such as gene expression in brain development.