Tead1 regulates the expression ofPeripheral Myelin Protein 22during Schwann cell development

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.

Transcriptional control of myelination and remyelination

“…Appearance or disappearance of transcription factors will alter its choice of cooperation partners and remove or add either antagonistic or synergistic influences. Stage‐specific changes in the regulatory network composition are likely also responsible for the multiple effects of the Hippo signaling components Yap and Taz on Schwann cell development in combination with Tead transcription factors, in particular Tead1, as their nuclear effectors (Deng et al, ; Grove et al, ; Lopez‐Anido et al, ; Poitelon et al, ).…”

“…Stage-specific changes in the regulatory network composition are likely also responsible for the multiple effects of the Hippo signaling components Yap and Taz on Schwann cell development in combination with Tead transcription factors, in particular Tead1, as their nuclear effectors (Deng et al, 2017;Grove et al, 2017;Lopez-Anido et al, 2016;Poitelon et al, 2016).…”

Influence of Mechanical Stimuli on Schwann Cell Biology

“…The first reports that studied YAP/TAZ in SCs in vivo confirmed that both mechanotransducers are active in SCs during axon-SC recognition, while SCs are myelinating and after completion of myelination (Poitelon et al, 2016 ; Deng et al, 2017 ; Grove et al, 2017 ). During development, YAP/TAZ regulates SC proliferation, differentiation and myelination programs (Lopez-Anido et al, 2016 ; Poitelon et al, 2016 ; Deng et al, 2017 ; Grove et al, 2017 ). SCs ablated for both YAP/TAZ show an arrest of proliferation, fail to associate with an axon and do not initiate myelination (Poitelon et al, 2016 ; Deng et al, 2017 ; Grove et al, 2017 ).…”

Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury

“…Consistent with this role, we and others have recently shown that YAP/TAZ promote vigorous proliferation of immature Schwann cells (SC) in developing peripheral nerves (Poitelon et al, 2016; Deng et al, 2017; Grove et al, 2017), and that overexpression of YAP/TAZ promotes tumorigenic proliferation of mature SCs in adult peripheral nerves (Mindos et al, 2017; Wu et al, 2018). Unexpectedly, several groups demonstrated that YAP or YAP/TAZ promote differentiation of developing SCs by upregulating myelin-associated genes, thereby mediating developmental myelination (Fernando et al, 2016; Lopez-Anido et al, 2016; Poitelon et al, 2016; Deng et al, 2017; Grove et al, 2017). Our group additionally showed that YAP/TAZ are selectively expressed in differentiated myelin-forming SCs, and that they are required for maintenance of the myelin sheath in adult nerves (Grove et al, 2017).…”