Abstract
Schwann cells (SCs) arise from neural crest cells (NCCs) that first give rise to SC precursors (SCPs), followed by immature SCs, pro-myelinating SCs, and finally, non-myelinating or myelinating SCs. After nerve injury, mature SCs ‘de-differentiate’, downregulating their myelination program while transiently re-activating early glial lineage genes. To better understand molecular parallels between developing and de-differentiated SCs, we characterized the expression profiles of a panel of 12 transcription factors from the onset of NCC migration through postnatal stages, as well as after acute nerve injury. Using Sox10 as a pan-glial marker in co-expression studies, the earliest transcription factors expressed in E9.0 Sox10+ NCCs were Sox9, Pax3, AP2α and Nfatc4. E10.5 Sox10+ NCCs coalescing in the dorsal root ganglia differed slightly, expressing Sox9, Pax3, AP2α and Etv5. E12.5 SCPs continued to express Sox10, Sox9, AP2α and Pax3, as well as initiating Sox2 and Egr1 expression. E14.5 immature SCs were similar to SCPs, except that they lost Pax3 expression. By E18.5, AP2α, Sox2 and Egr1 expression was turned off in the nerve, while Jun, Oct6 and Yy1 expression was initiated in pro-myelinating Sox9+/Sox10+ SCs. Early postnatal and adult SCs continued to express Sox9, Jun, Oct6 and Yy1 and initiated Nfatc4 and Egr2 expression. Notably, at all stages, expression of each marker was observed only in a subset of Sox10+ SCs, highlighting the heterogeneity of the SC pool. Following acute nerve injury, Egr1, Jun, Oct6, and Sox2 expression was upregulated, Egr2 expression was downregulated, while Sox9, Yy1, and Nfatc4 expression was maintained at similar frequencies. Notably, de-differentiated SCs in the injured nerve did not display a transcription factor profile corresponding to a specific stage in the SC lineage. Taken together, we demonstrate that uninjured and injured SCs are heterogeneous and distinct from one another, and de-differentiation recapitulates transcriptional aspects of several different embryonic stages.
Highlights
The two main glial cell types in the peripheral nervous system (PNS) are Schwann cells (SCs) and satellite glial cells
These stages are associated with distinct phases of SC development: (i) delamination of trunk neural crest cells (NCCs) from the dorsal neural tube (E9.0); (ii) migration of trunk NCCs along the ventral path to populate the developing dorsal root ganglia (DRG) and peripheral nerves (E10.5); (iii) association of SC precursors (SCPs) with developing axons (E12.5); (iv) maturation of SCPs into immature Schwann cell (iSC) (E14.5); (v) differentiation of a subset of iSCs into pro-myelinating SCs (E18.5) and (vi) terminal differentiation of iSCs into myelinating and non-myelinating SCs (P7/P65) [48] (Fig 1A–1F)
Sox9 induces a NCC phenotype [25], and its expression biases migrating NCCs towards glial and melanocyte lineage selection [26], whereas essential roles have only been documented at later developmental stages for the remaining transcription factors in the SC lineage: AP2α maintains a SCP fate, impeding the transition to an iSC [39], Pax3 regulates SC proliferation [52] and Nfatc4 acts synergistically with Sox10 to initiate Egr2 expression in SCs [45]
Summary
The two main glial cell types in the peripheral nervous system (PNS) are Schwann cells (SCs) and satellite glial cells. Remak cells can enclose several axons, while myelinating SCs surround and myelinate only a single axonal length. SCs play an essential role in peripheral nerve regeneration and restoration of nervous function post-injury [1]. One of the most remarkable features of adult SCs is their capacity to transiently revert to an undifferentiated and proliferative state following nerve injury. Previous work has collectively suggested that this de-differentiation process recapitulates SC development, such that ‘repair’ SCs resemble an embryonic immature Schwann cell (iSC) phenotype [10, 12]. The transcription factors that regulate this reversion to a reparative SC state are only partially understood
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