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

Miz1 （Myc相互作用锌指蛋白1）是Myc结合转录因子反激活基因，如周期蛋白依赖性激酶抑制剂p21cip1或p15ink4b，以及参与细胞-细胞和细胞-基质相互作用的基因，如整合素。当Myc与Miz1结合时，基因表达受到抑制。组成型Miz1基因敲除在E7.5天是致命的。在角质形成细胞的条件Miz1敲除中，我们可以发现1)毛囊形态发生和完整性受损，2)角质形成细胞的增殖和分化减少，3)DMBA/TPA乳头瘤的发育和生长延迟。增殖的减少和肿瘤发生的延迟依赖于p21cip1。整合素ß1和p21cip1是周围神经组织主要胶质细胞雪旺细胞髓鞘形成和再生过程中的重要因子。我们的初步数据显示，当小鼠90 （P90）至120 （P120）天大时，雪旺细胞中Miz1的条件敲除可诱导后肢神经病变。这个年龄的小鼠出现严重的运动限制，并表现出坐骨神经形态上的全面缺陷。由于P30天坐骨神经的结构不明显，因此不太可能是发育缺陷导致3月龄小鼠的急性神经病变。老年动物（> P120）症状消退，但显著的神经结构缺陷持续存在。该项目的目的是miz1依赖性神经病的现象学特征及其时间过程的分析，以及随后的潜在机制的分子分析。与此同时，我们将与慕尼黑弗里德里希·鲍尔研究所的Senderek教授合作，分析来自遗传性神经病变患者的一些患者中是否存在Miz1基因的变化。

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.