Search

Myelin sheath formation in the peripheral nervous system and the ensuing saltatory conduction rely on differentiated Schwann cells. We have previously shown that transition of Schwann cells from an immature into a differentiated state requires Brg1 that serves as the central energy generating subunit in two related SWI/SNF-type chromatin remodelers, the BAF and the PBAF complex. Here we used conditional deletion of Pbrm1 to selectively interfere with the PBAF complex in Schwann cells. Despite efficient loss of Pbrm1 early during lineage progression, we failed to detect any substantial alterations in the number, proliferation or survival of immature Schwann cells as well as in their rate and timing of terminal differentiation. As a consequence, postnatal myelin formation in peripheral nerves appeared normal. There were no inflammatory alterations in the nerve or other signs of a peripheral neuropathy. We conclude from our study that Pbrm1 and very likely the PBAF complex are dispensable for proper Schwann cell development and that Schwann cell defects previously observed upon Brg1 deletion are mostly attributable to altered or absent function of the BAF complex. [ABSTRACT FROM AUTHOR]

The three SoxD proteins, Sox5, Sox6 and Sox13, represent closely related transcription factors with important roles during development. In the developing nervous system, SoxD proteins have so far been primarily studied in oligodendroglial cells and in interneurons of brain and spinal cord. In oligodendroglial cells, Sox5 and Sox6 jointly maintain the precursor state, interfere with terminal differentiation, and thereby ensure the proper timing of myelination in the central nervous system. Here we studied the role of SoxD proteins in Schwann cells, the functional counterpart of oligodendrocytes in the peripheral nervous system. We show that Schwann cells express Sox5 and Sox13 but not Sox6. Expression was transient and ceased with the onset of terminal differentiation. In mice with early Schwann cell-specific deletion of both Sox5 and Sox13, embryonic Schwann cell development was not substantially affected and progressed normally into the promyelinating stage. However, there was a mild and transient delay in the myelination of the peripheral nervous system of these mice. We therefore conclude that SoxD proteins—in stark contrast to their action in oligodendrocytes—promote differentiation and myelination in Schwann cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

For differentiation, Schwann cells rely on the class III POU domain transcription factor Oct-6, which is expressed transiently when Schwann cells have established a one-to-one relation with axons but have not yet started to myelinate. Loss of Oct-6 leads to a transient arrest in this promyelinating stage and a delay in myelination. Although the closely related POU domain protein Brn-2 is coexpressed with Oct-6 in Schwann cells, its loss has only mild consequences. Combined loss of both POU domain proteins, in contrast, dramatically increases the myelination delay, raising the question of how related POU domain proteins compare to each other in their activities. Here, we have replaced Oct-6 expression in the mouse with expression of the class III POU domain protein Brn-1. Although this protein is not normally expressed in Schwann cells, Brn-1 was capable of fully replacing Oct-6. Brn-1 efficiently induced Krox-20 expression as a prerequisite for myelination. Onset and extent of myelination were also indistinguishable from that of the wild type in mice that carried only Brn-1 instead of Oct-6 alleles. Similar to Oct-6, Brn-1 down-regulated its own expression at later stages of myelination. Thus, class III POU domain proteins can fully replace each other in Schwann cell development. [ABSTRACT FROM AUTHOR]

Summary: Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of transcription factors. How this is linked to chromatin changes is not well understood. Here we show that the glial transcription factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the transcription factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination. [ABSTRACT FROM AUTHOR]