The Sox10 transcription factor is required to maintain as well as specify glial identity, adding new causes for the neuropathies associated with SOX10 mutations.

Specification of the myelin-forming oligodendrocytes of the central nervous system requires the Sox9 transcription factor, whereas terminal differentiation depends on the closely related Sox10. Between specification and terminal differentiation, Sox9 and Sox10 are co-expressed in oligodendrocyte precursors and are believed to exert additional functions. To identify such functions, we have deleted Sox9 specifically in already specified oligodendrocyte precursors of the spinal cord. In the absence of Sox9, oligodendrocyte precursors developed normally and started terminal differentiation on schedule. However, when Sox10 was additionally deleted, oligodendrocyte precursors exhibited an altered migration pattern and were present in reduced numbers because of increased apoptosis rates. Remaining precursors continued to express many characteristic oligodendroglial markers. Aberrant expression of astrocytic and neuronal markers was not observed. Strikingly, we failed to detect PDGF receptor alpha expression in the mutant oligodendrocyte precursors, arguing that PDGF receptor alpha is under transcriptional control of Sox9 and Sox10. Altered PDGF receptor alpha expression is furthermore sufficient to explain the observed phenotype, as PDGF is both an important survival factor and migratory cue for oligodendrocyte precursors. We thus conclude that Sox9 and Sox10 are required in a functionally redundant manner in oligodendrocyte precursors for PDGF-dependent survival and migration.

Sox proteins are widely believed to team up with other transcription factors as partner proteins to perform their many essential functions during development. In this study, yeast two-hybrid screens identified transcription factors as a major group of interacting proteins for Sox8 and Sox10. Interacting transcription factors were very similar for these two group E Sox proteins and included proteins with different types of DNA-binding domains, such as homeodomain proteins, zinc finger proteins, basic helix–loop–helix and leucine zipper proteins. In all cases analyzed, the interaction involved the DNA-binding domain of the transcription factor which directly contacted the C-terminal part of the high-mobility-group (HMG) domain. In particular, the C-terminal tail region behind helix 3 of the HMG domain was shown by mutagenesis to be essential for interaction and transcription factor recruitment. The HMG domain thus not only possesses DNA-binding and DNA-bending but also protein-interacting ability which may be equally important for the architectural function of Sox proteins on their target gene promoters.

The transcription factor Sox10 is expressed throughout Schwann cell development and has already been shown to be essential for specification and for the identity and further development of immature Schwann cells. Here, we show that Sox10 is also required in Schwann cells for establishing the myelinating state. This is concluded from the fact that a peripheral neuropathy develops in mice in which Sox10 is deleted by a Cre recombinase whose expression is under control of Krox20 regulatory elements. This neuropathy is characterized by altered marker gene expression along the peripheral nerve, decreased conductivity, and severe persistent hypomyelination. As the Cre recombinase is additionally active in boundary cap cells, we also analyzed the role of Sox10 during embryogenesis in establishment and maintenance of the boundary between central and peripheral nervous systems. Sox10 deletion did not affect establishment or survival of boundary cap cells but appeared to compromise barrier function as cells expressing oligodendrocyte and astrocyte markers were no longer restricted to the central nervous system, and instead found in peripheral nerves. We infer that in addition to its many roles in Schwann cells, Sox10 is also important for the integrity of the boundary between central and peripheral nervous systems.