Neuroscience Initiative, Advanced Science Research Center, CUNY, New York City, New York, USA.
Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York City, New York, USA.
Glia. 2022 Feb;70(2):321-336. doi: 10.1002/glia.24108. Epub 2021 Oct 23.
The N-myc downstream regulated gene family member 1 (NDRG1) is a gene whose mutation results in peripheral neuropathy with central manifestations. While most of previous studies characterized NDRG1 role in Schwann cells, the detection of central nervous system symptoms and the identification of NDRG1 as a gene silenced in the white matter of multiple sclerosis brains raise the question regarding its role in oligodendrocytes. Here, we show that NDRG1 is enriched in oligodendrocytes and myelin preparations, and we characterize its expression using a novel reporter mouse (TgNdrg1-EGFP). We report NDRG1 expression during developmental myelination and during remyelination after cuprizone-induced demyelination of the adult corpus callosum. The transcriptome of Ndrg1-EGFP+ cells further supports the identification of late myelinating oligodendrocytes, characterized by expression of genes regulating lipid metabolism and bioenergetics. We also generate a lineage specific conditional knockout (Olig1 ;Ndrg1 ) line to study its function. Null mice develop normally, and despite similar numbers of progenitor cells as wild type, they have fewer mature oligodendrocytes and lower levels of myelin proteins than controls, thereby suggesting NDRG1 as important for the maintenance of late myelinating oligodendrocytes. In addition, when control and Ndrg1 null mice are subject to cuprizone-induced demyelination, we observe a higher degree of demyelination in the mutants. Together these data identify NDRG1 as an important molecule for adult myelinating oligodendrocytes, whose decreased levels in the normal appearing white matter of human MS brains may result in greater susceptibility of myelin to damage.
N- 神经母细胞瘤衍生基因 1（NDRG1）是一种基因突变可导致周围神经病伴中枢表现的基因。虽然之前的大多数研究都描述了 NDRG1 在施万细胞中的作用，但中枢神经系统症状的检测以及 NDRG1 作为多发性硬化症大脑白质中沉默基因的鉴定，提出了其在少突胶质细胞中的作用问题。在这里，我们表明 NDRG1 在少突胶质细胞和髓鞘制剂中丰富，并使用新型报告小鼠（TgNdrg1-EGFP）对其表达进行了表征。我们报告了 NDRG1 在发育性髓鞘形成期间以及成年胼胝体中 cuprizone 诱导脱髓鞘后的再髓鞘化期间的表达。Ndrg1-EGFP+细胞的转录组进一步支持了晚期髓鞘形成少突胶质细胞的鉴定，其特征在于调节脂质代谢和生物能量的基因表达。我们还生成了一种谱系特异性条件性敲除（Olig1 ;Ndrg1 ）系来研究其功能。缺失小鼠正常发育，尽管其祖细胞数量与野生型相似，但它们的成熟少突胶质细胞数量较少，髓鞘蛋白水平较低，这表明 NDRG1 对于维持晚期髓鞘形成的少突胶质细胞很重要。此外，当对照和 Ndrg1 缺失小鼠受到 cuprizone 诱导的脱髓鞘时，我们观察到突变体中脱髓鞘程度更高。这些数据共同确定 NDRG1 是成年髓鞘形成少突胶质细胞的重要分子，其在人类多发性硬化症大脑正常外观白质中的水平降低可能导致髓鞘更容易受到损伤。
