PROJECT II: DAVID MORRIS - UNIVERSITY OF WASHINGTONFUNCTIONS OF THE FMRP ISOFORMSThere 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 differentbiochemical properties. Fragile X Syndrome (FXS) should therefore be considered to arise not from thelack of a single protein, but from the absence of a family of proteins with different biological functions. Anunderstanding of the biological roles of the FMRP isoforms is clearly critical in considering treating for thecondition. 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 fourisoforms 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) assaybehavioral endpoints in the recombinant mice in order to define differences between the individual proteinisoforms; (iii) carry out neurophysiological tests of long-term potentiation and long-term depression in brainregions 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 inprimary cultures established from the recombinant mice.
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