WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT

Abstract

Abstract WWC1 regulates episodic learning and memory, and genetic nucleotide polymorphism of WWC1 is associated with neurodegenerative diseases such as Alzheimer's disease. However, the molecular mechanism through which WWC1 regulates neuronal function remains unclear. Here, we show that WWC1 and its paralogs (WWC2/3) bind directly to angiomotin (AMOT) family proteins (Motins), and recruit USP9X to deubiquitinate and stabilize Motins. Deletion of WWC in different cell types, including neurons, leads to reduced protein levels of Motins. In mice, neuron-specific deletion of Wwc1 and Wwc2 results in lower density of the dendritic spine and impairment of cognitive functions. Interestingly, ectopic expression of AMOT partially rescues the neuronal phenotypes associated with Wwc1/2 deletion. Thus, WWC proteins modulate spinogenesis and cognition in part by regulating protein stability of Motins.