A Reciprocal Regulatory Loop Between TAZ/YAP and G protein Gas Regulates Schwann Cell Proliferation and Differentiation

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. Here, we show that a dual direct role for Hippo effectors TAZ and YAP in regulation of SC proliferation and myelination through modulating G protein expression and interacting with SOX10, respectively. Developmentally-regulated mutagenesis indicates that TAZ/YAP are critical for SC proliferation yet also required for their differentiation and myelination. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ and YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identified that TAZ targets and represses Gnas, encoding Gas-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks myelination in the sciatic nerve. Thus, our study revealed that the Hippo/TAZ/YAP and Gas-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis. Overall design: 3 Control Samples and 3 Mutant