The Transcription Factors Sox10 and Myrf Define an Essential Regulatory Network Module in Differentiating Oligodendrocytes

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.

Author Summary

In recent years it has become clear that complex developmental processes are not regulated by single transcription factors but rather by combinations of transcription factors that interact in intricate regulatory networks. Here, we analyze the regulatory network that drives terminal differentiation of oligodendrocytes, the cells of the vertebrate central nervous system that form myelin and thereby guarantee rapid saltatory conduction. We show that the transcription factor Myrf is directly activated by the transcription factor Sox10, and map a Sox10-responsive enhancer to an evolutionarily conserved element in intron 1 of the Myrf gene. We then go on to show that once induced, Myrf physically interacts and functionally cooperates with its inducer Sox10 to activate myelin genes arguing that the two jointly drive terminal differentiation of oligodendrocytes. With this study we define an essential module in the myelin-specific regulatory network in the central nervous system. By comparing this module with the corresponding module in Schwann cells of the peripheral nervous system which consists of Sox10 and the Krox20 transcription factor we furthermore conclude that myelination in the two compartments of the vertebrate nervous system is regulated by similarly organized, but differentially implemented regulatory networks.