Krox-20 controls myelination in the peripheral nervous system

Abstract

The molecular mechanisms controlling the process of myelination by Schwann cells remain elusive, despite recent progress in the identification and characterization of genes encoding myelin components (reviewed in ref. 1). We have created a null allele in the mouse Krox-20 gene, which encodes a zinc-finger transcription factor, by in-frame insertion of the Escherichia coli lacZ gene, and have shown that hindbrain segmentation is affected in Krox-20-/- embryos. We demonstrate here that Krox-20 is also activated in Schwann cells before the onset of myelination and that its disruption blocks Schwann cells at an early stage in their differentiation, thus preventing myelination in the peripheral nervous system. In Krox-20-/- mice, Schwann cells wrap their cytoplasmic processes only one and a half turns around the axon, and although they express the early myelin marker, myelin-associated glycoprotein, late myelin gene products are absent, including those for protein zero and myelin basic protein. Therefore Krox-20 is likely to control a set of genes required for completion of myelination in the peripheral nervous system.

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

“…mice [31] were backcrossed onto the BALB/c 6.5 + TCR background for nine generations. Embryos from heterozygous timed pregnancies were harvested on day 13.5.…”

Myelination and mTOR

“…The physiological decline in mTORC1 activity is therefore required to allow onset of SC myelination. On the molecular level, aberrantly high mTORC1 signaling impaired the timely upregulation of Krox20 (Egr2) expression (Figlia et al, 2017), the master transcription factor required for the onset of PNS myelination (Svaren & Meijer, 2008; Topilko et al, 1994). Downstream of mTORC1, S6K appears to be the responsible mediator by inhibiting transcriptionally Krox20 expression.…”

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).…”