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

组蛋白脱乙酰酶(HDAC)家族的染色质重塑酶是关键的转录调节因子，它可以通过去乙酰化组蛋白和去乙酰化非组蛋白靶标如转录因子来控制转录活性。我们先前已经证明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、维持和损伤后的再生过程中发挥关键作用。其他组也显示了HDAC3和HDAC4在SC髓鞘形成、脱分化和损伤后再髓鞘形成中的额外功能。在脊椎动物中，三叉神经节的轴突与SC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退化至关重要。此外，由干细胞构建的髓鞘对于轴突隔离和沿轴突的电信号快速传导是必不可少的。事实上，髓鞘疾病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，一大组遗传性周围神经病称为夏科-玛丽-图斯病，会导致三叉神经节脱髓鞘和/或轴突变性。PNS脱髓鞘也可以继发于感染(如格林-巴利综合征)、糖尿病、毒物、衰老或创伤性损伤。了解控制SC发展、成人维持和损伤后可塑性的机制对于阐明改善PNS修复的新疗法具有潜在的重要意义。此外，这些知识可以作为比较干细胞和少突胶质细胞之间的调控的基础，少突胶质细胞是中枢神经系统的髓鞘胶质细胞，并有助于识别潜在的关键差异，解释为什么干细胞可以促进轴突再生，而少突胶质细胞不能。我们发现，HDAC8是HDAC家族的另一个成员，在三叉神经节损伤后的发育和再生过程中，HDAC8在干细胞中强烈表达和调节。然而，HDAC8在这些过程中的作用迄今尚未报道。在本项目中，我们将阐明HDAC8在PNS发育过程中的SCs中的作用，以及在成人PNS完整性维持和损伤后PNS再生过程中的作用。根据这些结果，我们将测试体内增加或减少HDAC8活性是否会提高再生过程有效的年轻人和再生效率下降的老年小鼠的损伤后的再生效率。

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.