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

雪旺细胞条件性 Miz1 敲除后发生周围神经病变

基本信息

批准号：
234800982
负责人：
Professor Dr. Hans-Peter Elsässer
金额：
--
依托单位：
Institut für Klinische Zytobiologie und Zytopathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/234800982?language=en
关键词：
Development peripheral neuropathy after conditional

项目摘要

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.

Miz1（Myc 相互作用锌指蛋白 1）是一种 Myc 结合转录因子反式激活基因，如细胞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，如整联蛋白。当 Myc 与 Miz1 结合时，基因表达受到抑制。 Miz1 的组成型敲除在 E7.5 天是致命的。在角质形成细胞中条件性 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 乳头状瘤的发育和生长延迟。增殖的减少和肿瘤发生的延迟是 p21cip1 依赖性的。 Integrinß1 和 p21cip1 是雪旺细胞（周围神经组织的主要神经胶质细胞）髓鞘形成和再生过程中的重要因子。我们的初步数据表明，当小鼠 90 (P90) 至 120 (P120) 天大时，雪旺细胞中 Miz1 的条件性敲除会诱发后肢神经病变。这个年龄的小鼠出现严重的运动受限，并表现出坐骨神经形态上的全面缺陷。由于在第 P30 天，坐骨神经的结构不明显，因此发育缺陷不太可能导致 3 个月大的小鼠发生急性神经病变。在老年动物（> P120）中，尽管神经结构的显着缺陷仍然存在，但症状会消退。该项目的目的是对 Miz1 依赖性神经病进行现象学表征并分析其时间过程，以及随后对潜在机制进行分子分析。与此同时，我们将与慕尼黑 Friedrich Baur 研究所的 Senderek 教授合作，分析更多患有遗传性神经病的患者中的一些患者的 Miz1 基因是否存在变化。