The molecular machinery of myelin gene transcription in Schwann cells

Abstract

During late fetal life, Schwann cells in the peripheral nerves singled out by the larger axons will transit through a promyelinating stage before exiting the cell cycle and initiating myelin formation. A network of extra- and intracellular signaling pathways, regulating a transcriptional program of cell differentiation, governs this progression of cellular changes, culminating in a highly differentiated cell. In this review, we focus on the roles of a number of transcription factors not only in myelination, during normal development, but also in demyelination, following nerve trauma. These factors include specification factors involved in early development of Schwann cells from neural crest (Sox10) as well as factors specifically required for transitions into the promyelinating and myelinating stages (Oct6/Scip and Krox20/Egr2). From this description, we can glean the first, still very incomplete, contours of a gene regulatory network that governs myelination and demyelination during development and regeneration.

Figure 1. Outline of a gene regulatory network of myelin-associated Schwann cell differentiation

The major transcription factors involved in the promyelinating to myelinating transition are depicted with their regulatory relationship. Arrows indicate activation while blunt lines indicate repression. This regulatory pathway culminates in induction of several genes in myelinating Schwann cells, such as Myelin protein zero (Mpz), Myelin basic protein (Mbp), Connexin 32 (Cx32), and HMG CoA reductase. See text for further details.

Figure 2. The POU domain transcription factors Oct6/Scip and Brn2 regulate the timing and rate of the promyelin to myelinating transition

A. Toluodine Blue stained cross-sections of wildtype (left panel), Oct6 mutant (middle panel) and Oct6/Brn2 mutant nerves at 16 days of postnatal development. Double Oct6/Brn2 mutant Schwann cells are arrested at the promyelin stage of differentiation while around 70% of Oct6 mutant Schwann cells are stalled at this stage. In wildtype nerves all Schwann cell have gone on to myelinate their associated axon. B. Quantification of the promyelinating to myelinating transition. The graphical representation demonstrates the dramatic reduction in rate and altered kinetics of this cellular transition. Promyelin and myelin figures were counted in electron micrographs at 2600× magnification. At least 250 axons were scored per genotype at the indicated timepoint.

Figure 3. Sites of Krox20/Egr2 function

In panel A, the configuration of Krox20/Egr2 binding sites in the Connexin 32 and Mpz genes is diagrammed. The promoter element of Connexin 32 and intron element of Mpz are synergistically activated by Egr2 and Sox10, and similar configurations of sites are found in the Mbp and Mag genes. In panel B, various EGR2 mutations associated with human peripheral neuropathies are diagrammed. For exact details, refer to the Inherited Peripheral Neuropathies Mutation Database (http://www.molgen.ua.ac.be/CMTMutations/). Dominant mutations have been found in all three zinc fingers, and they generally impair DNA-binding by EGR2. In addition, a recessive mutation in the NAB-binding domain was identified in one family. Loss of NAB binding is expected to result in defective targeting of the NuRD chromatin remodeling complex.