MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR

Abstract

Abnormal dendritic complexity is a shared feature ofmany neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under- and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors invivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1null neurons, knocking down FLNA invivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1null neurons was dependent on MEK1/2 but not mTOR activity, despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1null neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner.