Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development

Hum Mol Genet. 2016 Jul 15;25(14):3055-3069. doi: 10.1093/hmg/ddw158. Epub 2016 Jun 10.

Abstract

Schwann cells are myelinating glia in the peripheral nervous system that form the myelin sheath. A major cause of peripheral neuropathy is a copy number variant involving the Peripheral Myelin Protein 22 (PMP22) gene, which is located within a 1.4-Mb duplication on chromosome 17 associated with the most common form of Charcot-Marie-Tooth Disease (CMT1A). Rodent models of CMT1A have been used to show that reducing Pmp22 overexpression mitigates several aspects of a CMT1A-related phenotype. Mechanistic studies of Pmp22 regulation identified enhancers regulated by the Sox10 (SRY sex determining region Y-box 10) and Egr2/Krox20 (Early growth response protein 2) transcription factors in myelinated nerves. However, relatively little is known regarding how other transcription factors induce Pmp22 expression during Schwann cell development and myelination. Here, we examined Pmp22 enhancers as a function of cell type-specificity, nerve injury and development. While Pmp22 enhancers marked by active histone modifications were lost or remodeled after injury, we found that these enhancers were permissive in early development prior to Pmp22 upregulation. Pmp22 enhancers contain binding motifs for TEA domain (Tead) transcription factors of the Hippo signaling pathway. We discovered that Tead1 and co-activators Yap and Taz are required for Pmp22 expression, as well as for the expression of Egr2 Tead1 directly binds Pmp22 and Egr2 enhancers early in development and Tead1 binding is induced during myelination, correlating with Pmp22 expression. The data identify Tead1 as a novel regulator of Pmp22 expression during development in concert with Sox10 and Egr2.

Publication types

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

MeSH terms

  • Animals
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • DNA Copy Number Variations / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Early Growth Response Protein 2 / biosynthesis
  • Early Growth Response Protein 2 / genetics*
  • Gene Expression Regulation / genetics
  • Humans
  • Mice
  • Myelin Proteins / genetics*
  • Myelin Sheath / genetics
  • Myelin Sheath / pathology
  • Neurogenesis / genetics
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Phenotype
  • SOXE Transcription Factors / genetics*
  • Schwann Cells / metabolism
  • Schwann Cells / pathology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Myelin Proteins
  • PMP22 protein, human
  • SOXE Transcription Factors
  • Sox10 protein, mouse
  • Tead1 protein, mouse
  • Transcription Factors