RPTP/RHO--A NOVEL RECEPTOR PROTEIN TYROSINE PHOSPHATASE

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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.