Abstract
Following peripheral nerve injury, transcription factors upregulated in the distal nerve play essential roles in Schwann cell reprogramming, fibroblast activation and immune cell function to create a permissive distal nerve environment for axonal regrowth. In this report, we first analysed four microarray data sets to identify transcription factors that have at least twofold upregulation in the mouse distal nerve stump at day 3 and day 7 post-injury. Next, we compared their relative mRNA levels through the analysis of an available bulk mRNA sequencing data set at day 5 post-injury. We then investigated the expression of identified TFs in analysed single-cell RNA sequencing data sets for the distal nerve at day 3 and day 9 post-injury. These analyses identified 55 transcription factors that have at least twofold upregulation in the distal nerve following mouse sciatic nerve injury. Expression profile for the identified 55 transcription factors in cells of the distal nerve stump was further analysed on the scRNA-seq data. Transcription factor network and functional analysis were performed in Schwann cells. We also validated the expression pattern of Jun, Junb, Runx1, Runx2, and Sox2 in the mouse distal nerve stump by immunostaining. The findings from our study not only could be used to understand the function of key transcription factors in peripheral nerve regeneration but also could be used to facilitate experimental design for future studies to investigate the function of individual TFs in peripheral nerve regeneration.
Highlights
Transcription factors (TFs) are DNA binding proteins that drive various biological processes such as embryonic development, tissue identity maintenance and tissue repair following injury (Zhou et al, 2017; Lambert et al, 2018)
Transcription Factor Upregulation in Nerves a peripheral nerve results in a rapid Schwann cell reprogramming, mesenchymal cell activation and resident macrophage phenotype transition in the distal nerve stump (Jessen and Mirsky, 2016, 2019; Carr et al, 2019; Toma et al, 2020). Immune cells such as neutrophils, macrophages, mast cells, T cells, natural killer (NK) cells, and B cells are all recruited into the distal nerve stump follow injury (Martini et al, 2008), and recruited immune cells are reprogrammed into a repair immune cell phenotype by the distal nerve regenerative microenvironment (Ydens et al, 2012, 2020; Davies et al, 2019)
One of the best-studied TFs in peripheral nerve regeneration is Jun and studies have shown that the upregulation of Jun in Schwann cells plays an essential role in reprograming adult Schwann cells into repair Schwann cells following peripheral nerve injury (Parkinson et al, 2008; Arthur-Farraj et al, 2012; Fontana et al, 2012)
Summary
Transcription factors (TFs) are DNA binding proteins that drive various biological processes such as embryonic development, tissue identity maintenance and tissue repair following injury (Zhou et al, 2017; Lambert et al, 2018). Injury to Transcription Factor Upregulation in Nerves a peripheral nerve results in a rapid Schwann cell reprogramming, mesenchymal cell activation and resident macrophage phenotype transition in the distal nerve stump (Jessen and Mirsky, 2016, 2019; Carr et al, 2019; Toma et al, 2020). The upregulation TFs in cells of the distal nerve play key roles in cell reprogramming, activation and phenotype transition to create a permissive distal nerve environment for axonal regrowth (Jessen and Mirsky, 2008; Arthur-Farraj et al, 2012; Doddrell et al, 2012; Fontana et al, 2012; Patodia and Raivich, 2012; Mindos et al, 2017; Roberts et al, 2017). One of the best-studied TFs in peripheral nerve regeneration is Jun and studies have shown that the upregulation of Jun in Schwann cells plays an essential role in reprograming adult Schwann cells into repair Schwann cells following peripheral nerve injury (Parkinson et al, 2008; Arthur-Farraj et al, 2012; Fontana et al, 2012)
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