The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development

Abstract

The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1 and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following damage. In this report we demonstrate the involvement of a third transcription factor, the POU domain factor Brn-2. We show that Schwann cells express Brn-2 in a developmental profile similar to that of Oct-6 and that Brn-2 gene activation does not depend on Oct-6. Overexpression of Brn-2 in Oct-6-deficient Schwann cells, under control of the Oct-6 Schwann cell enhancer (SCE), results in partial rescue of the developmental delay phenotype, whereas compound disruption of both Brn-2 and Oct-6 results in a much more severe phenotype. Together these data strongly indicate that Brn-2 function largely overlaps with that of Oct-6 in driving the transition from promyelinating to myelinating Schwann cells. The high conduction velocity of nerve fibers is a hallmark of the nervous system of higher vertebrates and depends on structural and molecular specializations that are elaborated during development. These specializations occur through intimate and continued interactions between the neuron and its associated glial cells and result in the elaboration by glial cells of myelin, the important membranous structure that ensheaths and insulates axons (Arroyo and Scherer 2000; Fields and StevensGraham 2002;Mirsky et al. 2002). Two glial cell types produce myelin: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Although very similarly organized, the molecular composition of CNS and PNS myelin differs significantly, and oligodendrocytes and Schwann cells have adopted different, but overlapping, sets of transcriptional regulators to coordinate myelogenesis (Hudson 2001; Topilko and Meijer 2001). These differences reflect their distinct embryonic origins. Whereas oligodendrocytes originate from the neuroepithelial precursors that line the lumen of the spinal cord and ventricles of the brain, Schwann cells derive mainly from the neural crest, a transient embryonic stem (ES) cell population that generates a wide variety of cell types including sensory and autonomic neurons and melanocytes (Le Douarin and Kalcheim 1999;Richardson 2001). Schwann cell precursors populate the early outgrowing nerve bundles, where they proliferate and segregate individual and groups of fibers until the number of Schwann cells and fibers is eventually matched. During the first few days of postnatal development, many Schwann cells establish a 1:1 relationship with axons, cease to proliferate, and initiate myelin formation such that by the end of the first postnatal week of development, all myelin-competent axons are actively being myelinated. Schwann cells that remain associated with groups of lower-caliber fibers will segregate these fibers in cytoplasmic cuffs without mye...

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

“…Transcription of the Dhh gene has not been studied, and the regulatory region that mediates its expression in Schwann cells has not yet been identified. However, work by Jaegle et al (2003) had shown that 19 kb of genomic sequence around the Dhh gene are sufficient to achieve expression of a Cre transgene in Schwann cells. This region encompasses all three Dhh exons as well as upstream and downstream sequences.…”

Misexpression of Pou3f1 Results in Peripheral Nerve Hypomyelination and Axonal Loss

“…The abil- ity of Brn-1 and Brn-2 to compensate for the loss of Pou3f1 was demonstrated using mutant knock-in mice in which Brn-1 (or Brn-2) was inserted into the Pou3f1 locus effectively replacing Pou3f1 expression. The Brn-1 knock-in mice displayed normal Egr2 expression and onset of myelination, whereas Brn-2 knock-in mice manifested a partial rescue of the aberrant myelination phenotype present in Pou3f1-deficient mice (Jaegle et al, 2003;Friedrich et al, 2005). These findings indicate that Brn-1 and Brn-2 are functionally capable of rescuing the myelination delay of the Pou3f1 null mice and provide additional evidence that, as previously hypothesized, Pou3f1 is required for the initiation of myelination (Jaegle and Meijer, 1998;Zorick et al, 1999).…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…Therefore, myelination is accompanied by the production of huge amounts of myelin proteins and lipids. The entry into the myelination program in Schwann cells is controlled on the transcriptional level by factors like Egr2 (Krox-20), Pou3f1 (Oct-6/Scip/Tst-1) and Pou3f2 (Brn2) that interact with Sox10 to drive expression of myelin genes (Topilko et al, 1994;Bermingham et al, 1996;Jaegle et al, 2003;Finzsch et al, 2010; see also Svaren and Meijer, 2008, and the references herein). In addition, lipid biosynthesis genes are coordinately regulated, and the Srebp/Scap transcription factors and the control of their expression play important roles in lipid production (Verheijen et al, 2009;Norrmen et al, 2014).…”