Rheb1在施旺细胞生成和外周神经髓鞘形成中的作用

A fundamental biological question in life science is how mature cell types are generated from precursor cells, so that a relevant organ can perform certain biological functions. In the peripheral nervous system (PNS), Schwann cells (SCs) produce myelin and also provide growth support to axons. The knowledge of molecular control of the differentiation of SCs remains incomplete. Our previous work indentifies Rheb1 (Ras-homolog enriched in brain) as a critical activator of mTORC1 and as a critical regulator of the differentiation of oligodendrocyte precursor cells in the central nervous system (CNS). While certain regulatory mechanisms underlying the formation of myelin producing cells are shared in the CNS and PNS, it is clear that some regulatory mechanisms function only in the PNS or CNS. Whether Rheb1 plays a similar role in the control of the formation and SCs and myelination in the PNS remains unknown. To examine the role of Rheb1 in the formation of SCs and myelination, we will generate mouse models where the activity of Rheb1 can be selectively inactivated (loss of function) or increased (gain of function) in SC precursors (SCPs) and examine the hypothesis that Rheb1 controls SC formation and myelination. Furthermore, we will examine the notion that Notch1 functions downstream of Rheb1 and mediates the effect of Rheb1 on SC formation and Rheb1 may be required for nuregulin to control SC formation and myelination. This study will provide important insights into the SC formation and peripheral myelination, and increase our understanding of the pathology of demyelinating neuropathies and nerve injury, and the development of relevant therapeutic interventions.

成熟细胞如何从其前体细胞分化而来形成相关组织器官发挥其生物学功能，一直是生命科学领域的基本问题。外周神经系统中，施旺细胞形成髓鞘并支持轴突生长，但调控施旺细胞分化的分子机制尚不完全清楚。我们前期发现Rheb1（在脑中高表达Ras同源蛋白）是mTORC1的重要激活分子并在中枢神经系统调节少突胶质前体细胞分化。有些分子在中枢和外周神经中都调节成髓细胞的产生，而有些只在外周或中枢单独发挥作用。Rheb1是否在外周神经施旺细胞和髓鞘生成中也发挥作用仍不清楚。为了检测Rheb1在该过程中的作用，我们将制备在施旺细胞前体中特异敲除或过表达Rheb1的转基因小鼠，同时检测Notch1是否介导Rheb1对施旺细胞生成的调节，以及Rheb1是否是NRG调控施旺细胞和髓鞘生成所必需。研究结果将揭示施旺细胞生成和外周神经髓鞘化过程。同时增进我们对脱髓鞘疾病和神经损伤的认知，为相关干预治疗药物的开发奠定基础。

髓鞘对于神经信号沿轴突高效传导必不可少，外周神经系统(PNS)是由施旺细胞包裹轴突形成髓鞘，但关于施旺细胞如何分化发育去包裹、分选轴突仍然还有许多不清楚的地方。我们实验室前期工作已证实，中枢神经系统(CNS)胶质细胞的Rheb1/mTor信号通路对于少突胶质细胞的分化发育及成髓的过程具有重要作用，本课题拟研究Rheb1/mTor信号通路对外周神经系统髓鞘发生与生成是否有类似的调控作用，为了探讨Rheb1在外周神经系统中的作用，我们构建了在施旺细胞中特异敲除Rheb1的小鼠，通过对其研究发现：Rheb1能通过调控髓鞘蛋白的合成与脂质的合成代谢，影响髓鞘的生成，并且还会参与到外周轴突分选过程，与中枢不同的是，Rheb1不能调控施旺细胞的分化。以上研究结果将揭示施旺细胞生成和外周神经髓鞘化过程新的机制，同时增进我们对脱髓鞘疾病和神经损伤的认知，为相关干预治疗药物的开发奠定基础。