Development of a peripheral neuropathy after a conditional Miz1 knockout in Schwann cells
Final Report Abstract
Miz1 (Myc interacting zinc finger protein 1) is a transcription factor containing a N-terminal POZ domain and 13 zinc finger domains in the middle and C-terminal part. Miz1 was originally identified as a Myc binding protein by a two hybrid screen and since then other Miz1 binding proteins have been identified. Binding of these proteins to Miz1 leads either, as in case of Myc, to a repression or to a stimulation of the Miz1 dependent transcription. Well known target genes of Miz1 are the cyclin dependent kinase inhibitors p15Ink4b, p21Cip1 and p57Kip2. Miz1 has pleiothrophic functions and plays a role in proliferation, differentiation, cell adhesion, apoptosis, autophagy and vesicular transport. The constitutive deletion is lethal at E7.5, but a cre/lox mouse model has been used to study the in vivo functions of Miz1 after conditional deletion of the Miz1 POZ domain (Miz1∆POZ), essential for DNA binding, in different tissues and organs. We described a complex skin phenotype after Miz1 POZ domain deletion in keratinocytes and unraveled a group of target genes involved in cell-cell or cell-matrix adhesion. Further, we could show that the incidence and growth of papilloma in the DMBA/TPA skin tumor model is reduced in a p21Cip1 dependent manner. Martin Eiler’s group in Würzburg used this model to study the function of Miz1 in neuronal cells of the central nervous system and described a cerebellar neurodegeneration based on a deranged autophagic flux in Purkinje cells. This conclusion was drawn from ChIP sequencing results, providing a list of direct Miz1 target genes many of which are associated with vesicular transport and autophagy. Finally, we found a lactation defect in mammary glands of Miz1∆POZ mice based on the attenuation of the Stat5 signaling pathway, most likely due to the down regulation of a similar group of Miz1 target genes as those identified in neuronal cells. Taken together, these studies expanded the list of Miz1 target genes, showed that many of these genes are associated with cell cycle regulation and vesicular transport and that the explicit function of Miz1 is cell type and context dependent.
Publications
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(2015). Late onset neuropathy with spontaneous clinical remission in mice lacking the POZ domain of the transcription factor Myc-interacting zinc finger protein 1 (Miz1) in Schwann cells. J. Biol. Chem. 290, 727–743
Sanz-Moreno, A., Fuhrmann, D., Zankel, A., Reingruber, H., Kern, L., Meijer, D., Niemann, A., and Elsässer, H.-P.
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(2015). Schwann cell Miz without POZ: degeneration meets regeneration. Neural Regen. Res. 10, 1563–1564
Fuhrmann, D., and Elsässer, H.-P.
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Miz1 POZ domain deletion in Schwann cells causes dedifferentiation and myelin outfoldings. Meeting of the Peripheral Nerve society in Quebec, 2015
Fuhrmann D, Sanz-Moreno A, Zankel A, Niemann A, Elsässer H-P
