Integration of Nuclear Receptors into a Schwann cell Gene Regulatory Network.

Peripheral nerve function depends on the proper formation and maintenance of Schwann cells. During development, large diameter axons are enveloped by single, myelinating Schwann cells whereas clusters of small diameter axons are surrounded by nonmyelinating Schwann cells in Remak bundles. The transcription factor SRY-box 10 (SOX10) is required for the development of Schwann cells, but its functions in different neural crest and glial lineages have shown that SOX10 commonly cooperates with other transcription factors to activate cell-specific gene programs. In a previous study, we compared SOX10-bound regulatory elements in Schwann cells and identified a specific enrichment for nuclear receptor motifs at SOX10 binding sites in Schwann cells. NR2F1 and NR2F2 (Coup-TFI/Coup-TFII) are expressed from neural crest through Schwann cell maturity, and knockdown of nuclear receptors Nr2f1 and Nr2f2 in primary Schwann cells downregulated several myelin genes. In this study, we have identified a NR2F-regulated target gene network in Schwann cells, which revealed enrichment for nonmyelinating Schwann cell genes. Cut&Run assays in S16 Schwann cells revealed novel, genome-wide binding sites of NR2F2 and two downstream transcription factors: 1) Retinoid X Receptor Gamma (RXRG), which is also expressed preferentially in nonmyelinating Schwann cells, and 2) TEA-Domain factor (TEAD1), which is an important HIPPO pathway component required for Remak bundle formation. Our study elucidates the transcriptional cooperation that programs the regulatory network in nonmyelinating Schwann cells.