Functions of HDAC8 in Schwann cells during development, maintenance and regeneration of the peripheral nervous system

组蛋白去乙酰化酶（HDAC）家族的染色质重塑酶是关键的转录调节因子，它可以通过使组蛋白去乙酰化来控制转录活性，也可以通过使转录因子等非组蛋白靶点去乙酰化来控制转录活性。我们之前已经证明，HDAC家族的两个成员HDAC1和HDAC2 （HDAC1/2）在周围神经系统（PNS）的髓鞘胶质细胞雪旺细胞（SCs）的发育、维持和病变后再生过程中发挥关键作用。其他组也显示HDAC3和HDAC4在SC损伤后髓鞘形成、去分化和再髓鞘形成中的其他功能。在脊椎动物中，PNS的轴突与SCs相互作用。这些相互作用对于保护轴突免受外部环境的影响并防止其降解至关重要。此外，由SCs构建的髓磷脂对于轴突绝缘和沿轴突快速传导电信号至关重要。事实上，髓磷脂紊乱可以在人类的各种情况下发生，并可能导致严重的残疾。例如，一大群被称为Charcot-Marie-Tooth病的遗传性周围神经病变会导致PNS脱髓鞘和/或轴突变性。PNS脱髓鞘也可继发于感染（如吉兰-巴勒综合征）、糖尿病、有毒物质、衰老或创伤性病变。了解控制成人SC发育、维持和损伤后可塑性的机制，对于制定改善PNS修复的新疗法具有潜在的重要意义。此外，这些知识可以为比较SCs和中枢神经系统的髓鞘胶质细胞（oligodendrocytes, OLs）之间的调控奠定基础，并有助于确定潜在的关键差异，解释为什么SCs可以促进轴突再生，而OLs不能。我们发现HDAC家族的另一成员HDAC8在PNS病变后的发育和再生过程中在SCs中得到强烈表达和调控。然而，HDAC8在这些过程中的功能迄今尚未报道。在本项目中，我们将阐明HDAC8在PNS发育过程中、成人PNS完整性的维持以及病变后PNS再生过程中的作用。根据这些结果，我们将测试在体内增加或减少HDAC8活性是否能提高年轻成人（再生过程有效）和老年小鼠（再生效率下降）损伤后的再生效率。

Chromatin-remodeling enzymes of the histone deacetylase (HDAC) family are key transcriptional regulators, which can control transcriptional activity by deacetylating histones and also by deacetylating non-histone targets such as transcription factors.We have previously shown that the two members of the HDAC family HDAC1 and HDAC2 (HDAC1/2) play a key role in Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), during PNS development, maintenance and regeneration after lesion. Other groups have also shown additional functions for HDAC3 and HDAC4 in SC myelination, de-differentiation and remyelination after lesion.In vertebrates, axons of the PNS interact with SCs. These interactions are critical to protect axons from the external environment and prevent their degradation. In addition, myelin built by SCs is essential for axonal insulation and for fast conduction of electric signals along axons. Indeed, myelin disorders can occur in various cases in humans and can lead to severe disabilities. For instance, a large group of inherited peripheral neuropathies called Charcot-Marie-Tooth disease leads to PNS demyelination and/or axonal degeneration. PNS demyelination can also be secondary to an infection (e.g. Guillain-Barré syndrome), to diabetes, toxic agents, aging, or to a traumatic lesion.Understanding the mechanisms that control SC development, maintenance in adults and plasticity after lesion is of potential major importance to elaborate new therapies for the improvement of PNS repair. In addition, this knowledge can constitute a basis for the comparison of regulations between SCs and oligodendrocytes (OLs), the myelinating glia of the central nervous system, and help identifying potential critical differences explaining why SCs can promote axonal regeneration whereas OLs cannot.We found that HDAC8, another member of the HDAC family, is robustly expressed and regulated in SCs during development and regeneration after a PNS lesion. The functions of HDAC8 in these processes have however not been reported so far. In this project, we will elucidate the functions of HDAC8 in SCs during PNS development, in the maintenance of PNS integrity in adults and in the regeneration process of the PNS after lesion. Depending on these results, we will test whether increasing or decreasing HDAC8 activity in vivo enhances regeneration efficiency after lesion in young adults where the regeneration process is efficient and in aged mice where regeneration efficiency declines.