RPTP/RHO--A NOVEL RECEPTOR PROTEIN TYROSINE PHOSPHATASE

描述（改编自申请人摘要）：情感障碍， 精神病和智力迟钝是一组精神健康疾病 被认为部分是由于正常发育的中断， 神经系统内的过程。 病理生理学的基础 精神和行为障碍是指 由遗传异常或不利环境产生的特性 例如疾病或药物滥用。 这种分子破坏可能导致 细胞间相互作用的变化导致各种缺陷， 从神经管室畸形到不适当的突触 阵 我们克隆了一个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 它是一种发育调节分子， 在小鼠小脑皮质中定义了一个清晰的前后边界 在胚胎的中脑和后脑之间。 在 除了它们在细胞内信号传导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转导， RPTP分子与各种细胞粘附机制有关， 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， 作为细胞接触现象的直接信号转换器。 我们建议通过执行一系列 实验分为四个具体目标。 第一个目标是产生 抗RPTP-rho抗体用于免疫细胞化学定位 RPTP-rho蛋白在光镜和电镜水平。 第二 目的是研究胞外区在细胞内的作用， 聚集和细胞粘附。 在第三个目标中，RPTP-rho的作用 胞内结构域通过与 将研究钙粘蛋白/连环蛋白。 最后，在第四个具体目标中， RPTP-rho启动子将被克隆、测序并用 目的是为鉴定负责的序列提供基础 对于RPTP-rho转录物在小鼠中不同的喙尾分布， 小脑皮层和未来的基因失活研究。 拟议 研究将阐明RPTP-rho在大脑中的发育作用， 提示发育性神经精神病新的分子机制 紊乱

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.