Ep400 deficiency in Schwann cells causes persistent expression of early developmental regulators and peripheral neuropathy

Franziska Fröb,Anna-Lena Saur,Simone Hillgärtner,Rikiro Fukunaga,Trevor J Williams,Ernst R Tamm,Elisabeth Sock,Toshihiro Fujii,Michael Wegner

doi:10.1038/s41467-019-10287-w

Abstract

Schwann cells ensure efficient nerve impulse conduction in the peripheral nervous system. Their development is accompanied by defined chromatin changes, including variant histone deposition and redistribution. To study the importance of variant histones for Schwann cell development, we altered their genomic distribution by conditionally deleting Ep400, the central subunit of the Tip60/Ep400 complex. Ep400 absence causes peripheral neuropathy in mice, characterized by terminal differentiation defects in myelinating and non-myelinating Schwann cells and immune cell activation. Variant histone H2A.Z is differently distributed throughout the genome and remains at promoters of Tfap2a, Pax3 and other transcriptional regulator genes with transient function at earlier developmental stages. Tfap2a deletion in Ep400-deficient Schwann cells causes a partial rescue arguing that continued expression of early regulators mediates the phenotypic defects. Our results show that proper genomic distribution of variant histones is essential for Schwann cell differentiation, and assign importance to Ep400-containing chromatin remodelers in the process.

Highlights

Schwann cells ensure efficient nerve impulse conduction in the peripheral nervous system
Our results argue that altered genomic H2A.Z distribution leads to a failure to shut off early developmental regulators whose continued presence in differentiating Schwann cells (SCs) interferes with the maturation and myelination process
As Oct[6] is a marker of pro-myelinating SCs20,21, these results argue that SC development in Ep400ΔPNS mice proceeded into this stage

Summary

Introduction

Schwann cells ensure efficient nerve impulse conduction in the peripheral nervous system Their development is accompanied by defined chromatin changes, including variant histone deposition and redistribution. To study the importance of variant histones for Schwann cell development, we altered their genomic distribution by conditionally deleting Ep400, the central subunit of the Tip60/Ep400 complex. SC development from neural crest cells is coordinated by sets of transcriptional regulators with defined windows of expression[1] These include Tfap2a and Pax[3] in the early neural crest and SC precursor stages, Sox[2] in the immature, and Oct[6] in the pro-myelinating stage as well as Krox[20] as a central regulator of the final differentiation and myelination process[2]. Our results argue that altered genomic H2A.Z distribution leads to a failure to shut off early developmental regulators whose continued presence in differentiating SCs interferes with the maturation and myelination process

Methods

Results

Conclusion