Die Funktion des Transkriptionsfaktors Miz1 in Schwann-Zellen des peripheren Nervensystems

The differentiation and myelination of Schwann cells, the glial cells of the peripheral nervous system (PNS), is based on the fine-tuned transcriptional regulation mediated by diverse transcription factors and chromatin-modifiers. Miz1 (MYC-interacting zing finger protein 1) belongs to the family of BTB/POZ-zing finger transcription factors and is involved in the control of cellular processes, such as cell cycle, apoptosis, differentiation, vesicular trafficking and autophagy. The stable interaction of Miz1 with chromatin depends on a tetramerization via its N-terminal POZ-domain. In the present study the POZ-domain of Miz1 was deleted in mice, specifically in the Schwann cells of the peripheral nervous system (Miz1∆POZ), using a Cre-lox-system. As a result, adult Miz1∆POZ-animals at the age of 90 days (P90), developed a peripheral neuropathy characterized by signs of paralysis and motor deficits and ultra-structurally by a de- and dysmyelination of the myelin sheath of peripheral axons. Interestingly, after an approximately one-month-lasting period of severe disabilities, Miz1∆POZ-nerves revealed signs of spontaneous regeneration and remyelination, achieving an almost entire compensation of neurological symptoms. Molecular biological analysis was able to identify early transcriptional expression changes in Miz1∆POZ-Schwann cells in P30 mice. Notably, the postnatal development of peripheral nerves is completed at this age and ultra-structural or neurological differences could not yet be detected between control and Miz1∆POZ-animals. Genome-wide transcriptome-analysis of sciatic nerves at P30 using RNA-sequencing-technology (RNA-seq) revealed a set of upregulated genes involved in the regulation of cell cycle and cell division processes. In line with this observation, a slowly growing population of Schwann cells persisted in the cell cycle in Miz1∆POZ-nerves, whereas a complete cell cycle exit was enforced in control Schwann cells. Furthermore, in vitro and in vivo ChIP-experiments demonstrated that, amongst the initially deregulated genes identified by RNA-seq, the expression of the histone 3-lysine(K)-demethylase Kdm8 is directly controlled via Miz1. Miz1 represses the expression of Kdm8, most likely as part of the final postnatal differentiation of Schwann cells, which goes along with their exit from the cell cycle. In agreement with this observation, KDM8 stimulated the proliferation of Schwann cells via the demethylation of H3K36me2. The presented data suggest that cell cycle associated genes are repressed by an increasing H3K36-di-methylation towards the 3’UTR under control conditions. Conversely, this inhibition seems to be abrogated in Miz1∆POZ-nerves as a consequence of an augmented demethylation by KDM8. This is the first time that Miz1 and the epigenetic regulation of H3K36me2 by KDM8 is linked to the development of Schwann cells and the pathogenesis of peripheral neuropathies.