Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells

Abstract

Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.

The Dual-specificity phosphatase Dusp15 is regulated by Sox10 and Myrf in Myelinating Oligodendrocytes

“…2A). Furthermore, overexpression of Sox10 in oligodendroglial cells led to strongly increased numbers of Dusp15-positive cells in the spinal cord of E18.5-old Rosa26 stopflox-tTA Sox10::Cre 2xTetSox10 mice (Weider et al, 2015) (Fig. 2B,C).…”

“…The following alleles were used: TetSox10 (Weider et al, 2015), Sox10 fl (Finzsch et al, 2010), Rosa26 stopflox-tTA (Wang et al, 2008), Sox10::Cre (Matsuoka et al, 2005), Brn4::Cre (Ahn et al, 2001), and Dusp15-lacZ. The following alleles were used: TetSox10 (Weider et al, 2015), Sox10 fl (Finzsch et al, 2010), Rosa26 stopflox-tTA (Wang et al, 2008), Sox10::Cre (Matsuoka et al, 2005), Brn4::Cre (Ahn et al, 2001), and Dusp15-lacZ.…”

“…The following alleles were used: TetSox10 (Weider et al, 2015), Sox10 fl (Finzsch et al, 2010), Rosa26 stopflox-tTA (Wang et al, 2008), Sox10::Cre (Matsuoka et al, 2005), Brn4::Cre (Ahn et al, 2001), and Dusp15-lacZ. After genotyping, material from E18.5 embryos and pups underwent fixation in 4% paraformaldehyde, cryopreservation and sectioning before X-gal staining (Weider et al, 2015), immunohistochemistry or in situ hybridization on 10 lm thick sections. Transgenic animals were produced by standard procedures and allowed to develop until postnatal day 7.…”

Direct reprogramming of somatic cells: an update

“…Using in situ gene therapy strategies with direct reprogramming factors, some preclinical trials with a mouse model were successful in the conversion of various cerebral cell types into neurons (Heinrich and Rouaux, 2015). By enhanced expression of Sox10 in Satellite Glial cells, Weider et al (2015) successfully induced these cells in vivo into oligodendrocyte-like cells (Weider et al, 2015).…”

Oligodendroglial heterogeneity in time and space (NG2 glia in the CNS)

“…Additional crucial regulators are the helix-loop-helix protein Mash1/Ascl1, the zinc finger protein Sip1 and the homeodomain protein Nkx2.2. New studies give first insights into the complex interactions of these transcription factors inside the gene-regulatory network that involves antagonistic as well as synergistic and inductive relations and establish a variety of control circuits, which additionally are influenced by the exact amount of the corresponding transcription factor, post-translational modifications and epigenetic factors [10,11]. Currently, there is insufficient knowledge how the gene regulatory network in NG2 glia during development differs from the adult CNS.…”