The Role of FMRP in the Regulation of PI3-Kinase Signaling in the Fragile X Mouse Model Open Access

Yim, So Young (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/1n79h4869?locale=en
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Abstract

Abstract
The Role of FMRP in the Regulation of PI3-Kinase Signaling in the Fragile X Mouse Model
By So Yim

A fundamental yet unexplained phenotype of animal models for the mental retardation disease fragile X syndrome (FXS) is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs) and dysregulated protein synthesis. FXS is caused by the inherited loss of Fragile X Mental Retardation Protein (FMRP), an mRNA binding protein that can inhibit the translation of select target mRNAs and control protein synthesis dependent synaptic plasticity. Preliminary data from the Bassell lab indicates that one specific downstream pathway of gp1 mGluRs, the PI3K signaling pathway, is regulated by FMRP and is overly active in FXS. We thus hypothesized that FMRP directly regulates PI3K activity, leading to exaggerated PI3K signaling in the absence of FMRP. To assess PI3K signaling, we first quantified Akt levels in dendrites and at synaptic membranes from wild type and FMRP deficient mice by immunocytochemistry of hippocampal neurons and western blot analyses of biochemical purifications of synaptic membrane fractions. Akt is translocated to the plasma membrane via its interaction with phosphoinositide-3-phosphates (PI3P), the product of PI3K activity. We observed an increase of Akt protein in dendrites of cultured Fmr1 KO neurons, as well as upregulated membrane levels of Akt in Fmr1 KO cortical synaptic fractions, indicating enhanced PI3K enzymatic activity in the absence of FMRP. Furthermore, our study suggests that FMRP directly regulates the protein expression of the PI3K enhancer PIKE-L. Our results show that PIKE-L protein levels are increased in synaptic fractions of Fmr1 KO mice, and that PIKE-L mRNA associates with FMRP in cortical lysates. My study has significant implications for the FXS field because it (1) points to novel therapeutic strategies for FXS by targeting excess PI3K activity, and (2) validates the PI3K activator PIKE as an important FMRP target playing a role for dysregulated gp1 mGluR signaling in FXS.

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Contents
Introduction.....................1 Methods..........................8 Results...........................13 Discussion.......................18 References......................26 Figures...........................31

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