Functions of the FMRP Isoforms

项目二：大卫莫里斯-华盛顿大学

PROJECT II: DAVID MORRIS - UNIVERSITY OF WASHINGTON FUNCTIONS OF THE FMRP ISOFORMS There are multiple isoforms of the Fragile X Mental Retardation Protein (FMRP). These isoforms, generated by alternative processing of the primary transcript from the Fmr1 gene, possess different biochemical properties. Fragile X Syndrome (FXS) should therefore be considered to arise not from the lack of a single protein, but from the absence of a family of proteins with different biological functions. An understanding of the biological roles of the FMRP isoforms is clearly critical in considering treating for the condition. The following specific aims address this question using mice in which cDNAs have been "knocked in" the Fmr1 gene, yielding animals that express only one of the isoforms. The choice of four isoforms for initial study was based on abundance and diversity of biochemical properties. We propose to: (i) define general aspects of the phenotypes of mice expressing individual FMRP isoforms; (ii) assay behavioral endpoints in the recombinant mice in order to define differences between the individual protein isoforms; (iii) carry out neurophysiological tests of long-term potentiation and long-term depression in brain regions where differences between wild-type and knockout animals have been previously defined; and (iv) examine trafficking of the individual FMRP isoforms in dentritic processes extended from neurons in primary cultures established from the recombinant mice.