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The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes.

Hornig J, Fröb F, Vogl MR, Hermans-Borgmeyer I, Tamm ER, Wegner M - PLoS Genet. (2013)

Bottom Line: Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes.This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination.Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented.

View Article: PubMed Central - PubMed

Affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Myelin is essential for rapid saltatory conduction and is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In both cell types the transcription factor Sox10 is an essential component of the myelin-specific regulatory network. Here we identify Myrf as an oligodendrocyte-specific target of Sox10 and map a Sox10 responsive enhancer to an evolutionarily conserved element in intron 1 of the Myrf gene. Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes. This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination. Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented.

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Histological analysis of myelination after CNS-specific Sox10 deletion and consequences of combined deletion of Sox8 and Sox10 on myelin gene expression.(A–C) Light microscopy of 1 µm semi-thin sections of the spinal cord ventral horn in wildtype (wt) (A) and Sox10ΔCNS (ko) mice (B,C) at P14 following Richardson's stain. Myelinated axons are stained in the white matter (WM) of the wildtype, but not the mutant. Sections from Sox10ΔCNS mice contain myelin only in the anterior rootlet (AR) where it is formed by Schwann cells. C represents a higher magnification of the area boxed in B. GM, grey matter. Scale bars, 100 µm. (D–F) Transmission electron microscopy of the wildtype spinal cord ventral horn at P14 shows myelinated axons (D, black arrows) around an OL (OL) in the white matter. In contrast, OL in Sox10ΔCNS mice are surrounded by axons that lack myelin sheaths (E,F, black arrows). In mutant mice only Schwann cells in the anterior rootlet have formed myelin sheaths (F, white arrow). Scale bars, 2.5 µm. (G–R) Differentiating OL were visualized by in situ hybridization on transverse spinal cord sections from the forelimb region of wildtype (wt) (G,H,K,L,O,P) or Sox10ΔCNS Sox8lacZ/lacZ (dko) (I,J,M,N,Q,R) mice at P7 (G,I,K,M,O,Q), and P16 (H,J,L,N,P,R) using antisense probes against Mbp (G–J), Plp (K–N), and Myrf (O–R). Ventral horn region is shown. Scale bar, 200 µm.
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pgen-1003907-g002: Histological analysis of myelination after CNS-specific Sox10 deletion and consequences of combined deletion of Sox8 and Sox10 on myelin gene expression.(A–C) Light microscopy of 1 µm semi-thin sections of the spinal cord ventral horn in wildtype (wt) (A) and Sox10ΔCNS (ko) mice (B,C) at P14 following Richardson's stain. Myelinated axons are stained in the white matter (WM) of the wildtype, but not the mutant. Sections from Sox10ΔCNS mice contain myelin only in the anterior rootlet (AR) where it is formed by Schwann cells. C represents a higher magnification of the area boxed in B. GM, grey matter. Scale bars, 100 µm. (D–F) Transmission electron microscopy of the wildtype spinal cord ventral horn at P14 shows myelinated axons (D, black arrows) around an OL (OL) in the white matter. In contrast, OL in Sox10ΔCNS mice are surrounded by axons that lack myelin sheaths (E,F, black arrows). In mutant mice only Schwann cells in the anterior rootlet have formed myelin sheaths (F, white arrow). Scale bars, 2.5 µm. (G–R) Differentiating OL were visualized by in situ hybridization on transverse spinal cord sections from the forelimb region of wildtype (wt) (G,H,K,L,O,P) or Sox10ΔCNS Sox8lacZ/lacZ (dko) (I,J,M,N,Q,R) mice at P7 (G,I,K,M,O,Q), and P16 (H,J,L,N,P,R) using antisense probes against Mbp (G–J), Plp (K–N), and Myrf (O–R). Ventral horn region is shown. Scale bar, 200 µm.

Mentions: Myelin gene expression in the postnatal Sox10ΔCNS spinal cord was analyzed by in situ hybridization with Mbp and Plp probes. At P3, Mbp- or Plp-positive cells were rarely seen in the mutant white matter, while present in substantial numbers in the wildtype (compare Figure 1A,I to Figure 1E,M). At P7, Mbp- and Plp-positive cells had increased in the Sox10ΔCNS spinal cord, but were still much fewer than in the wildtype (compare Figure 1B,J to Figure 1F,N). This trend persisted: The number of Mbp- and Plp-expressing cells in Sox10ΔCNS mice continued to increase, but their number failed to catch up with the wildtype until time of death (compare Figure 1C,D,K,L to Figure 1G,H,O,P). Histological and ultrastructural analyses of spinal cord white matter from Sox10ΔCNS mice at P14 failed to detect myelinated axons (compare Figure 2A with Figure 2B, Figure 2D with Figure 2E). The only myelin present in Sox10ΔCNS mice was in PNS structures such as spinal nerve rootlets and produced by Sox10-expressing Schwann cells (Figure 2B,C,F).


The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes.

Hornig J, Fröb F, Vogl MR, Hermans-Borgmeyer I, Tamm ER, Wegner M - PLoS Genet. (2013)

Histological analysis of myelination after CNS-specific Sox10 deletion and consequences of combined deletion of Sox8 and Sox10 on myelin gene expression.(A–C) Light microscopy of 1 µm semi-thin sections of the spinal cord ventral horn in wildtype (wt) (A) and Sox10ΔCNS (ko) mice (B,C) at P14 following Richardson's stain. Myelinated axons are stained in the white matter (WM) of the wildtype, but not the mutant. Sections from Sox10ΔCNS mice contain myelin only in the anterior rootlet (AR) where it is formed by Schwann cells. C represents a higher magnification of the area boxed in B. GM, grey matter. Scale bars, 100 µm. (D–F) Transmission electron microscopy of the wildtype spinal cord ventral horn at P14 shows myelinated axons (D, black arrows) around an OL (OL) in the white matter. In contrast, OL in Sox10ΔCNS mice are surrounded by axons that lack myelin sheaths (E,F, black arrows). In mutant mice only Schwann cells in the anterior rootlet have formed myelin sheaths (F, white arrow). Scale bars, 2.5 µm. (G–R) Differentiating OL were visualized by in situ hybridization on transverse spinal cord sections from the forelimb region of wildtype (wt) (G,H,K,L,O,P) or Sox10ΔCNS Sox8lacZ/lacZ (dko) (I,J,M,N,Q,R) mice at P7 (G,I,K,M,O,Q), and P16 (H,J,L,N,P,R) using antisense probes against Mbp (G–J), Plp (K–N), and Myrf (O–R). Ventral horn region is shown. Scale bar, 200 µm.
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pgen-1003907-g002: Histological analysis of myelination after CNS-specific Sox10 deletion and consequences of combined deletion of Sox8 and Sox10 on myelin gene expression.(A–C) Light microscopy of 1 µm semi-thin sections of the spinal cord ventral horn in wildtype (wt) (A) and Sox10ΔCNS (ko) mice (B,C) at P14 following Richardson's stain. Myelinated axons are stained in the white matter (WM) of the wildtype, but not the mutant. Sections from Sox10ΔCNS mice contain myelin only in the anterior rootlet (AR) where it is formed by Schwann cells. C represents a higher magnification of the area boxed in B. GM, grey matter. Scale bars, 100 µm. (D–F) Transmission electron microscopy of the wildtype spinal cord ventral horn at P14 shows myelinated axons (D, black arrows) around an OL (OL) in the white matter. In contrast, OL in Sox10ΔCNS mice are surrounded by axons that lack myelin sheaths (E,F, black arrows). In mutant mice only Schwann cells in the anterior rootlet have formed myelin sheaths (F, white arrow). Scale bars, 2.5 µm. (G–R) Differentiating OL were visualized by in situ hybridization on transverse spinal cord sections from the forelimb region of wildtype (wt) (G,H,K,L,O,P) or Sox10ΔCNS Sox8lacZ/lacZ (dko) (I,J,M,N,Q,R) mice at P7 (G,I,K,M,O,Q), and P16 (H,J,L,N,P,R) using antisense probes against Mbp (G–J), Plp (K–N), and Myrf (O–R). Ventral horn region is shown. Scale bar, 200 µm.
Mentions: Myelin gene expression in the postnatal Sox10ΔCNS spinal cord was analyzed by in situ hybridization with Mbp and Plp probes. At P3, Mbp- or Plp-positive cells were rarely seen in the mutant white matter, while present in substantial numbers in the wildtype (compare Figure 1A,I to Figure 1E,M). At P7, Mbp- and Plp-positive cells had increased in the Sox10ΔCNS spinal cord, but were still much fewer than in the wildtype (compare Figure 1B,J to Figure 1F,N). This trend persisted: The number of Mbp- and Plp-expressing cells in Sox10ΔCNS mice continued to increase, but their number failed to catch up with the wildtype until time of death (compare Figure 1C,D,K,L to Figure 1G,H,O,P). Histological and ultrastructural analyses of spinal cord white matter from Sox10ΔCNS mice at P14 failed to detect myelinated axons (compare Figure 2A with Figure 2B, Figure 2D with Figure 2E). The only myelin present in Sox10ΔCNS mice was in PNS structures such as spinal nerve rootlets and produced by Sox10-expressing Schwann cells (Figure 2B,C,F).

Bottom Line: Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes.This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination.Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented.

View Article: PubMed Central - PubMed

Affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Myelin is essential for rapid saltatory conduction and is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In both cell types the transcription factor Sox10 is an essential component of the myelin-specific regulatory network. Here we identify Myrf as an oligodendrocyte-specific target of Sox10 and map a Sox10 responsive enhancer to an evolutionarily conserved element in intron 1 of the Myrf gene. Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes. This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination. Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented.

Show MeSH
Related in: MedlinePlus