RPTP/RHO--A NOVEL RECEPTOR PROTEIN TYROSINE PHOSPHATASE

描述(摘自申请者的摘要)：情感障碍， 精神病和精神发育迟滞是一组心理健康疾病 人们认为，部分原因是正常发育的中断 神经系统内的过程。的病理生理学基础 精神和行为障碍是基本分子的变化 由基因异常或不利环境产生的特性 例如疾病或药物滥用。这样的分子分裂可能会导致 在细胞间相互作用的变化中导致各种缺陷 从神经管室畸形到异常突触 队形。我们克隆了一种新的受体样蛋白酪氨酸 磷酸酶(RPTP-RHO)，其表达完全限于 中枢神经系统。它是一种发育调节的分子， 在小鼠小脑皮质中确定一个清晰的前后边界 在来自胚胎中脑和后脑的区域之间。在……里面 除了它们在细胞内信号中普遍接受的作用之外 通过调节蛋白质酪氨酸磷酸化进行信号转导， RPTP分子参与了多种细胞黏附机制， 包括细胞-细胞或细胞-细胞外基质识别和轴突 指导。RPTP-Rho的序列表明分子中的成员 作为细胞接触现象的直接信号换能器的家族。 我们建议通过执行一系列操作来扩展我们的初步数据 实验分为四个具体目标。第一个目标是生成 抗RPTP-Rho抗体免疫细胞化学定位 RPTP-Rho蛋白在光镜和电子显微镜下的表达。第二 目的是研究细胞外结构域在细胞中的作用 聚集和细胞黏附。在第三个目标中，RPTP-Rho的作用 结合蛋白参与信号转导的胞内结构域 钙粘附素/连环蛋白将被研究。最后，在第四个具体目标中， RPTP-RHO启动子将被克隆、测序并用 旨在为确定相关序列提供依据 对于RPTP-Rho转录本在轮状尾部的明显分布 小脑皮质和未来的基因失活研究。建议数 研究将阐明RPTP-Rho在大脑中的发育作用，并可能 提示发育性神经精神疾病的新分子机制 精神错乱。

DESCRIPTION (Adapted from applicant's abstract): Affective disorders, psychosis and mental retardation are a group of mental health diseases thought to result, in part, from the disruption of normal developmental processes within the nervous system. Fundamental to the pathophysiology of mental and behavioral disorders are alterations in basic molecular properties produced by genetic abnormalities or by unfavorable environments such as disease or substance abuse. Such molecular disruptions could result in changes in cell-cell interactions leading to a variety of defects ranging from malformation of neural tube compartments to inappropriate synapse formation. We have cloned a novel receptor-like protein tyrosine phosphatase (RPTP-rho) whose expression is entirely restricted to the central nervous system. It is a developmentally regulated molecule which defines a sharp anterior-posterior boundary in the murine cerebellar cortex between regions derived from the embryonic mes- and metencephalon. In addition to their generally accepted role in intracellular signal transduction through the regulation of protein tyrosine phosphorylation, RPTP molecules have been implicated in various cell adhesion mechanisms, including cell-cell or cell-extracellular matrix recognition and axon guidance. The sequence of RPTP-rho suggests membership in a molecular family which acts as direct signal transducers of cell contact phenomena. We propose to extend our preliminary data by performing a series of experiments grouped into four specific aims. The first aim is to generate anti-RPTP-rho antibodies for the immunocytochemical localization of the RPTP-rho protein at the light and electron microscopic levels. The second aim is to investigate the role of the extracellular domain in cell aggregation and cell adhesion. In the third aim, the role of the RPTP-rho intracellular domain in signal transduction via association with cadherins/catenins will be studied. Finally, in the fourth specific aim, the RPTP-rho promotor will be cloned, sequenced and characterized with a view to providing the basis for the identification of sequences responsible for the distinct rostrocaudal distribution of the RPTP-rho transcript in the cerebellar cortex and for future gene inactivation studies. The proposed studies will clarify the developmental role of RPTP-rho in the brain and may indicate new molecular mechanisms underlying developmental neuropsychiatric disorders.