Temporal Analysis of Gene Expression in the Murine Schwann Cell Lineage and the Acutely Injured Postnatal Nerve

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.

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

“…Rather, it appears that SCs, like CNS glia, produce Cxcl10 in an IFN-γ-independent fashion (47), because we found that Cxcl10 expression in 2-month Dhh-Cre Nf1 fl/fl nerve/DRG localized to cell clusters expressing SC-associated genes. This finding is consistent with prior work showing that transient Raf hyperactivation in SCs can induce Cxcl10 expression (48,49). Consistent with Raf/Ras/MEK/ERK pathway signaling contributing to Cxcl10 expression in SCs, Cxcl10 expression was negatively correlated with Nf1 expression in the SC clusters and positively correlated with the expression of AP-1 transcription factors and of downstream targets induced by Ras signaling.…”

Tonsil-Derived Mesenchymal Stem Cells Differentiate into a Schwann Cell Phenotype and Promote Peripheral Nerve Regeneration

“…However, the expression of another immediate early gene, KROX24 , was highest in T-MSC-SCs. In accordance with that reported by other studies, KROX20 and KROX24 were expressed in a successive and mutually exclusive manner [32,33,34]. Krox20 promotes the differentiation of SCs to a myelinating phenotype while Krox24 is a non-myelinating SC marker [33].…”

“…In accordance with that reported by other studies, KROX20 and KROX24 were expressed in a successive and mutually exclusive manner [32,33,34]. Krox20 promotes the differentiation of SCs to a myelinating phenotype while Krox24 is a non-myelinating SC marker [33]. Krox20 and Krox24 are playing antagonistic roles during the development of the SC lineage [34].…”

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…The derepressed level of these transcription factors was not sufficient to drive significant levels of neuronal gene expression, however. A number of homeobox genes ( Hoxa7 , Hoxa10 , Hoxd1 3) and neural crest transcription factors ( Pax3, Tfap2a, Tfap2b ) that are expressed in early SC development (Balakrishnan et al 2016; Doddrell et al 2012) were also induced at a low level. Interestingly, a number of transcription factors involved in oligodendrocyte development ( Nkx6.2, Nkx6.1, Myrf ) were also somewhat elevated (Mitew et al 2013), but did not drive induction of unique oligodendrocyte genes (Lopez-Anido et al 2015) in the Eed cKO.…”