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

Nat Commun. 2017 Apr 26;8:15161. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Chromogranins / biosynthesis
  • Chromogranins / metabolism*
  • GTP-Binding Protein alpha Subunits, Gs / biosynthesis
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Sheath / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Rats
  • Repressor Proteins / metabolism
  • SOXE Transcription Factors / metabolism*
  • Schwann Cells / metabolism*
  • Transcription Factor HES-1 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Chromogranins
  • Hes1 protein, mouse
  • Hes5 protein, mouse
  • Phosphoproteins
  • Repressor Proteins
  • SOXE Transcription Factors
  • Sox10 protein, mouse
  • Transcription Factor HES-1
  • Wwtr1 protein, mouse
  • Yap protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Gnas protein, mouse
  • GTP-Binding Protein alpha Subunits, Gs