Raghu Ramesh (Ph.D.)
Published: 2023
Total Pages: 0
Get eBook
Schwann cells are important glia in the peripheral nerve that myelinate axons and allow for rapid nerve conduction. Myelinating Schwann cells align and wrap around large diameter motor axons, whereas non-myelinating Schwann cells envelop bundles of small diameter sensory axons with their membranes. Schwann cells also play critical roles after peripheral nerve injury by performing tasks such as clearing myelin debris, recruiting macrophages, forming axon-guiding Bands of Bungner and re-myelinating new axons. Schwann cells undergo transcriptional and epigenomic remodeling to transdifferentiate from a myelinating state into a repair state that expresses a distinct set of genes not expressed in development. The transcription factor SOX10 is required for glial fate differentiation in the peripheral nerve and spinal cord. Transcription factors expressed in myelinating Schwann cells are not cell-specific, therefore interactions between transcription factor pairs drive Schwann cell differentiation. The nuclear receptor NR2F2 is co-expressed with SOX10 from early development in the neural crest through Schwann cell maturity, and NR2F2 motifs are enriched at peripheral nerve-specific SOX10-bound enhancers. Using siRNA knockdown, RNA-seq, and Cut&Run, we found that NR2F2 binds to and regulates non-myelinating Schwann cell genes and co-binds with RXRG and TEAD1 to form distinct transcriptional complexes at SOX10-bound, peripheral nerve enhancers. Many of the genes activated in the repair state transition in Schwann cells are associated with dynamically regulated enhancers that are not present during myelination, but appear after nerve injury. The AP-1 family member JUN is important for the induction for injury genes. To determine the extent to which JUN binds injury-induced enhancers, we incorporated ChIP-seq data and found that JUN binds to a significant proportion of injury-induced enhancers. Sonic Hedgehog (Shh) is a strongly induced injury gene and a target of JUN regulation. We found that JUN binds at three upstream injury-induced enhancers. Deletion of these Shh enhancers strongly downregulated the transcript post-injury in vivo, and these enhancers are activated by JUN overexpression in vitro. Due to the importance of Schwann cells in myelination and nerve regeneration, determining transcriptional mechanisms that mediate cellular processes is crucial for understanding debilitating nerve injuries, myelinopathies, and hereditary neuropathies.