A reciprocal regulatory loop between TAZ/YAP and G-protein G\u03b1s regulates Schwann cell proliferation and myelination

Yaqi Deng,Haibo Wang,Jincheng Wang,Mei Xin,Chuntao Zhao,Lingli Xu,Lai Man Natalie Wu,Shujun Bai,Wenhao Zhou,Q Richard Lu,Masahide Sakabe

doi:10.1038/ncomms15161

Abstract

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 role for Hippo effectors TAZ and YAP in 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 and differentiation in a stage-dependent manner. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ/YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identify that TAZ targets and represses Gnas, encoding Gαs-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks peripheral myelination. Thus, the Hippo/TAZ/YAP and Gαs-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis.

Highlights

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer
Our studies with SC lineagespecific and developmentally regulated mutagenesis approaches indicate that Hippo signalling effectors transcriptional co-activator with PDZ-binding-motif (TAZ)/YAP are required for SC proliferation, radial sorting and differentiation
A recent study suggested that dysmyelination in mutants in which Taz/Yap were deleted using the P0-Cre line are mainly due to radial sorting defects[22]

Summary

Introduction

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. We show that a dual role for Hippo effectors TAZ and YAP in SC proliferation and myelination through modulating G-protein expression and interacting with SOX10, respectively. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ/YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. The extrinsic and intrinsic signals that modulate and balance positive and negative factors to control SC proliferation and their transition to a differentiating state during peripheral myelination are not fully understood. TAZ/YAP activity can be regulated by multiple signalling pathways, including G-protein coupled receptors (GPCR), Transforming growth factor (TGF-b), wingless/integrated (WNT), and NOTCH, and by mechanical stimuli[19,20,21,22]. Whether YAP/TAZ have a direct role in the transition from SC proliferation-to-differentiation remains unresolved

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Results

Conclusion