Genetic rescue of a mouse model of Fragile X by targeted deletion of RICTOR

Fragile X syndrome is the most common heritable form of intellectual disabilities and a leading genetic cause of autism, caused by mutation of the gene encoding FMRP. Researchers have not found an effective treatment for the cognitive and social interaction deficits associated with fragile X. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, survival, translation and the actin cytoskeleton. mTOR is a kinase that integrates external cues and forms two distinct complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2), which have distinct functions and downstream targets. Whereas mTORC1 is a central regulator of cap-dependent translation, mTORC2 is a pivotal regulator of the actin cytoskeleton, spine structure and memory. Dysregulation of mTORC1 in fragile X syndrome is well established, but a role for mTORC2 is still unclear.

Suzanne Zukin and her colleagues have preliminary data showing that cofilin and its upstream regulator Rac1, a Rho GTPase implicated in spine structure and identified target of the Drosophila homolog of FMRP, are dysregulated in a mouse model of fragile X (FMR1 knockout mice), linking mTOR to cofilin signaling. Zukin and her colleagues hypothesize that overactivation of mTORC2 is causally related to synaptic defects in fragile X syndrome. They will test whether deletion of RICTOR, a component of mTORC2, can rescue mTORC2, Rac/PAK and cofilin signaling and spine defects in the somatosensory cortex of FMR1 knockout mice. They will use both conditional genetic deletion and acute short hairpin RNA knockdown of RICTOR in FMR1 knockout mice. These translational studies will create a foundation for generating therapeutic strategies to ameliorate fragile X syndrome.