Angiomotin links ROCK and YAP signaling in mechanosensitive differentiation of neural stem cells
Phillip Kang, David V. Schaffer, Sanjay Kumar
Abstract
Mechanical cues regulate the function of a broad range of stem cells in culture and in tissue. For example, soft substrates promote the neuronal differentiation of neural stem cells (NSCs) by suppressing cytoskeletal contractility. However, the mechanisms that link cytoskeletal signaling to the transcriptional regulatory processes that ultimately govern stiffness-dependent NSC fate commitment are not fully understood. Here, we show that Angiomotin (AMOT), which can bind both F-actin and the neurosuppressive transcriptional coactivator Yes-associated protein (YAP), is critical for mechanotransduction in NSCs. On soft substrates, loss of AMOT substantially reduces neurogenesis, whereas on stiff substrates, loss of AMOT negates the rescue of neurogenesis normally induced by pharmacologic inhibition of myosin activity. Furthermore, overexpression of a phospho-mimetic S175E AMOT mutant, which has been established to enhance AMOT-YAP binding, increases β-catenin activity and rescues neurogenesis on stiff substrates. Together, our data identify AMOT as an important intermediate signal transducer that allows NSCs to sense and respond to extracellular stiffness cues.