Oligodendrocytes are myelin-forming glia that ensheath the axons of neurons in the CNS. Recent studies have revealed that Wnt/β-catenin signaling plays important roles in oligodendrocyte development and myelin formation. However, there are conflicting reports on the specific function of Wnt signaling components in oligodendrocyte specification and differentiation. In the present study, we demonstrate that activation of β-catenin in neural progenitor cells before gliogenesis inhibits the generation of oligodendrocyte progenitors (OLPs) in mice. Once OLPs are formed, β-catenin becomes necessary for oligodendrocyte differentiation. Disruption of β-catenin signaling instead leads to a significant delay of oligodendrocyte maturation. These findings suggest that Wnt/β-catenin pathway regulates oligodendrocyte development in a stage-dependent manner.

Glial cells in the central nervous system (CNS) are composed of oligodendrocytes, astrocytes and microglia. They contribute more than half of the total cells of the CNS, and are essential for neural development and functioning. Studies on the fate specification, differentiation, and functional diversification of glial cells mainly rely on the proper use of cell- or stage-specific molecular markers. However, as cellular markers often exhibit different specificity and sensitivity, careful consideration must be given prior to their application to avoid possible confusion. Here, we provide an updated overview of a list of well-established immunological markers for the labeling of central glia, and discuss the cell-type specificity and stage dependency of their expression.

Myelin sheath formed by oligodendrocytes (OLs) is essential for the rapid propagation of action potentials in the vertebrate CNS. Myelin regulatory factor (MYRF) is one of the critical factors that control OL differentiation and myelin maintenance. Previous studies showed that MYRF is a membrane-bound transcription factor associated with the endoplasmic reticulum (ER). After self-cleavage, the N-fragment of MYRF is released from the ER and translocated into the nucleus where it functions as a transcription factor to activate myelin gene expression. At present, it remains unknown whether MYRF self-cleavage and functional activation can be regulated during OL differentiation. Here, we report that TMEM98, an ER-associated transmembrane protein, is capable of binding to the C-terminal of MYRF and inhibiting its self-cleavage and N-fragment nuclear translocation. In the developing CNS, TMEM98 is selectively expressed in early maturing OLs in mouse pups of either sex. Forced expression of TMEM98 in embryonic chicken spinal cord of either sex suppresses endogenous OL differentiation and MYRF-induced ectopic expression of myelin genes. These results suggest that TMEM98, through inhibiting the self-cleavage of MYRF, functions as a negative feedback regulator of MYRF in oligodendrocyte differentiation and myelination.SIGNIFICANCE STATEMENTMYRF protein is initially synthesized as an ER-associated membrane protein that undergoes autoproteolytic cleavage to release the N-fragment, which is then transported into the nucleus and activates the transcription of myelin genes. To date, the molecular mechanisms that regulate the self-cleavage and function of MYRF in regulating oligodendrocyte differentiation have remained unknown. In this study, we present the molecular and functional evidence that TMEM98 membrane protein physically interacts with MYRF in the ER and subsequently blocks its self-cleavage, N-terminal nuclear translocation, and functional activation of myelin gene expression. To our knowledge, this is the first report on the regulation of MYRF self-proteolytic activity and function by an interacting protein, providing new insights into the molecular regulation of OL differentiation and myelinogenesis.

: Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) with <10% 5-year survival rate. The growth and invasion of GBM cells into normal brain make the resection and treatment difficult. A better understanding of the biology of GBM cells is crucial to the targeted therapies for the disease. In this study, we identified Septin9 (SEPT9) and Septin2 (SEPT2) as GBM-related genes through integrated multi-omics analysis across independent transcriptomic and proteomic studies. Further studies revealed that expression of SEPT9 and SEPT2 was elevated in glioma tissues and cell lines (A172, U87-MG). Knockdown of SEPT9 and SEPT2 in A172/U87-MG was able to inhibit GBM cell proliferation and arrest cell cycle progression in the S phase in a synergistic mechanism. Moreover, suppression of SEPT9 and SEPT2 decreased the GBM cell invasive capability and significantly impaired the growth of glioma xenografts in nude mice. Furthermore, the decrease in GBM cell growth caused by SEPT9 and SEPT2 RNAi appears to involve two parallel signaling pathway including the p53/p21 axis and MEK/ERK activation. Together, our integration of multi-omics analysis has revealed previously unrecognized synergistic role of SEPT9 and SEPT2 in GBM, and provided novel insights into the targeted therapy of GBM.