Development of a peripheral neuropathy after a conditional Miz1 knockout in Schwann cells

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Miz1 (Myc interacting zinc finger protein 1) is a Myc-binding transcription factor transactivating genes like cyclin-dependent kinase inhibitors p21cip1 or p15ink4b, as well as genes involved in cell-cell and cell-matrix interaction like integrins. Gene expression is repressed when Myc binds to Miz1. A constitutive Miz1 knockout is lethal at day E7.5. In a conditional Miz1 knockout in keratinocytes we could show that 1) hair follicle morphogenesis and integrity was impaired, 2) proliferation and differentiation of keratinocytes was reduced and 3) the development and growth of DMBA/TPA papilloma was delayed. Reduction of proliferation and delay in tumorigenesis was p21cip1 dependent. Integrinß1 and p21cip1 are important factors during myelination and regeneration in Schwann cells, the major glial cells of the peripheral nervous tissue. Our preliminary data show that the conditional knockout of Miz1 in Schwann cells induce a neuropathy of the hind limbs when mice are 90 (P90) to 120 (P120) days old. Mice of this age develop severe motoric restraints and exhibit morphologically comprehensive defects of the sciatic nerve. Since at day P30 the structure of the sciatic nerve is inconspicuous, it is unlikely that a developmental defect causes the acute neuropathy in 3month old mice. In older animals (> P120) the symptoms regress, although significant defects of the nerve structure persist.Aim of the project is the phenomenological characterization of the Miz1-dependend neuropathy and the analysis of its time course, as well as the subsequent molecular analysis of the underlying mechanism. In parallel we will analyze in collaboration with Prof. Senderek, from the Friedrich Baur Institute in Munich, whether there are changes in the Miz1 gene present in some patients from a larger collection of patients suffering from hereditary neuropathies.