少突胶质细胞环指蛋白 Rnf43 是少突胶质细胞成熟所必需的损伤特异性调节蛋白。

Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation.

机构信息

Department of Neurology, University of California at San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California at San Francisco, San Francisco, CA 94158, USA; Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China; Institute of Brain and Intelligence, Third Military Medical University, Chongqing 400038, China.

Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.

出版信息

Neuron. 2021 Oct 6;109(19):3104-3118.e6. doi: 10.1016/j.neuron.2021.07.018. Epub 2021 Aug 13.

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.

少突胶质细胞（OL）在人类白质损伤中的成熟阻滞，显著导致多发性硬化症（MS）和新生儿脑损伤（如缺氧缺血性脑病（HIE））中内源性髓鞘再生的失败，这些损伤会导致脑瘫。在这项研究中，我们确定了一种少突胶质细胞内在因子，该因子可特异性控制损伤环境中的 OL 成熟。我们发现，在正常发育过程中不需要环指蛋白 Rnf43，但在新生鼠缺氧损伤和成年哺乳动物中枢神经系统的髓鞘再生中需要 Rnf43。Rnf43 而非相关的 Znrf3 可被 Wnt 信号在 OL 祖细胞（OPC）中强烈激活，并在人类 MS 和 HIE 中标记激活的 OPC。Rnf43 在损伤特异性环境中是必需的，它通过负向调节细胞表面 Fzd1 受体表达水平上的 Wnt 信号强度，促进 OPC 分化。使用 UM206 抑制 Fzd1 可促进体外和体内脱髓鞘损伤后的髓鞘再生。