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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.

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