YAP/TAZ initiate and maintain Schwann cell myelination.

Matthew Grove,Shin H Kang,Mary F Barbe,Jinbin Zhai,Michel A Lemay,Seung Baek Han,Raehee Park,Seo-Hee Cho,Jennifer Y Cho,Young-Jin Son,Alexander J Krupka,Michele Harris,Maryline Santerre,Seonhee Kim,Bassel E Sawaya,Hyukmin Kim

doi:10.7554/elife.20982

Abstract

Nuclear exclusion of the transcriptional regulators and potent oncoproteins, YAP/TAZ, is considered necessary for adult tissue homeostasis. Here we show that nuclear YAP/TAZ are essential regulators of peripheral nerve development and myelin maintenance. To proliferate, developing Schwann cells (SCs) require YAP/TAZ to enter S-phase and, without them, fail to generate sufficient SCs for timely axon sorting. To differentiate, SCs require YAP/TAZ to upregulate Krox20 and, without them, completely fail to myelinate, resulting in severe peripheral neuropathy. Remarkably, in adulthood, nuclear YAP/TAZ are selectively expressed by myelinating SCs, and conditional ablation results in severe peripheral demyelination and mouse death. YAP/TAZ regulate both developmental and adult myelination by driving TEAD1 to activate Krox20. Therefore, YAP/TAZ are crucial for SCs to myelinate developing nerve and to maintain myelinated nerve in adulthood. Our study also provides a new insight into the role of nuclear YAP/TAZ in homeostatic maintenance of an adult tissue.

Highlights

Normal motor and sensory functions depend on myelination of peripheral axons by myelin-forming Schwann cells that enables fast neural transmission
We found that adult Schwann cells (SCs) expressed both YAP and TAZ, because YAP/TAZ immunoreactivity was eliminated in Yap/Taz double conditional knockout (cKO), but not in Yap or Taz single cKO (Figure 1—figure supplement 1B, see Figure 2—figure supplement 1A and B)
Transcriptionally active, nuclear YAP/TAZ have not been detected in fully differentiated cells in adult tissues, and nuclear exclusion of YAP/TAZ is widely regarded as requisite for maintaining homeostasis in differentiated cells and tissues (Piccolo et al, 2014; Varelas, 2014)

Summary

Introduction

Normal motor and sensory functions depend on myelination of peripheral axons by myelin-forming Schwann cells (ie., myelinating SCs; mSCs) that enables fast neural transmission. Research over the last few decades has made great progress in identifying extra- and intracellular signals that drive SC differentiation and myelination during development, but mechanisms that maintain mSCs and myelination in adults remain unclear (recent reviews in Jessen et al, 2015; Salzer, 2015; Monk et al, 2015; Taveggia, 2016). Krox ( called Egr2) has been identified as the master transcription factor that drives myelin gene expression for both myelin formation and maintenance (Topilko et al, 1994; Decker et al, 2006). It remains unclear how extra- and intracellular signals regulate transcription of Krox. Several transcription factors upstream of Krox have been identified, they either reside only in the nucleus or play uncertain roles in Krox regulation (Stolt and Wegner, 2016)

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Conclusion