NG2 cells (also known as polydendrocytes) are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes and microglia. They can be identified by the expression of the proteoglycan NG2, have a highly branched morphology and are distributed throughout the grey and white matter. They differentiate into oligodendrocytes in vitro and have often been equated with oligodendrocyte precursor cells. However, whether polydendrocytes are multipotential cells that can give rise to neurons and astrocytes as well as oligodendrocytes is now highly debated. Furthermore, electrophysiological studies indicate that polydendrocytes receive synaptic input from neurons, suggesting that they are integrated in the neural network. This Review highlights recent findings and unresolved questions related to the lineage and function of polydendrocytes in the CNS.

SUMMARYNG2-expressing glia (NG2 cells, polydendrocytes) appear in the embryonic brain, expand perinatally, and persist widely throughout the gray and white matter of the mature central nervous system. We have previously reported that NG2 cells generate oligodendrocytes in both gray and white matter and a subset of protoplasmic astrocytes in the gray matter of the ventral forebrain and spinal cord. To investigate the temporal changes in NG2 cell fate, we generated NG2creER TM BAC transgenic mice, in which tamoxifen-inducible Cre is expressed in NG2 cells. Cre induction at embryonic day 16.5, postnatal day (P) 2, P30 and P60 in mice that were double transgenic for NG2creER TM BAC and the Cre reporter revealed that NG2 cells in the postnatal brain generate only NG2 cells or oligodendrocytes, whereas NG2 cells in the embryonic brain generate protoplasmic astrocytes in the gray matter of the ventral forebrain in addition to oligodendrocytes and NG2 cells. Analysis of cell clusters from single NG2 cells revealed that more than 80% of the NG2 cells in the P2 brain give rise to clusters consisting exclusively of oligodendrocytes, whereas the majority of the NG2 cells in the P60 brain generate clusters that contain only NG2 cells or a mixture of oligodendrocytes and NG2 cells. Furthermore, live cell imaging of single NG2 cells from early postnatal brain slices revealed that NG2 cells initially divide symmetrically to produce two daughter NG2 cells and that differentiation into oligodendrocytes occurred after 2-3 days.

Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA-derived RNAs (SHOTRNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER − breast cancer, AR − prostate cancer, or other examined cancer cell lines from other tissues. ER-dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated anticodon cleavage, which is promoted by sex hormones and their receptors. Resultant 5′-and 3′-SHOT-RNAs, corresponding to 5′-and 3′-tRNA halves, bear a cyclic phosphate (cP) and an amino acid at the 3′-end, respectively. By devising a "cP-RNA-seq" method that is able to exclusively amplify and sequence cP-containing RNAs, we identified the complete repertoire of 5′-SHOT-RNAs. Furthermore, 5′-SHOT-RNA, but not 3′-SHOT-RNA, has significant functional involvement in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis of hormone-dependent cancers and implicate SHOT-RNAs as potential candidates for biomarkers and therapeutic targets.tRNA | tRNA half | sex hormone | breast cancer | prostate cancer

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Spinal cord injury (SCI) induces a centralized fibrotic scar surrounded by a reactive glial scar at the lesion site. The origin of these scars is thought to be perivascular cells entering lesions on ingrowing blood vessels and reactive astrocytes, respectively. However, two NG2-expressing cell populations, pericytes and glia, may also influence scar formation. In the periphery, new blood vessel growth requires proliferating NG2 pericytes; if this were also true in the CNS, then the fibrotic scar would depend on dividing NG2 pericytes. NG2 glial cells (also called oligodendrocyte progenitors or polydendrocytes) also proliferate after SCI and accumulate in large numbers among astrocytes in the glial scar. Their effect there, if any, is unknown. We show that proliferating NG2 pericytes and glia largely segregate into the fibrotic and glial scars, respectively; therefore, we used a thymidine kinase/ganciclovir paradigm to ablate both dividing NG2 cell populations to determine whether either scar was altered. Results reveal that loss of proliferating NG2 pericytes in the lesion prevented intralesion angiogenesis and completely abolished the fibrotic scar. The glial scar was also altered in the absence of acutely dividing NG2 cells, displaying discontinuous borders and significantly reduced GFAP density. Collectively, these changes enhanced edema, prolonged hemorrhage, and impaired forelimb functional recovery. Interestingly, after halting GCV at 14 d postinjury, scar elements and vessels entered the lesions over the next 7 d, as did large numbers of axons that were not present in controls. Collectively, these data reveal that acutely dividing NG2 pericytes and glia play fundamental roles in post-SCI tissue remodeling. Spinal cord injury (SCI) is characterized by formation of astrocytic and fibrotic scars, both of which are necessary for lesion repair. NG2 cells may influence both scar-forming processes. This study used a novel transgenic mouse paradigm to ablate proliferating NG2 cells after SCI to better understand their role in repair. For the first time, our data show that dividing NG2 pericytes are required for post-SCI angiogenesis, which in turn is needed for fibrotic scar formation. Moreover, loss of cycling NG2 glia and pericytes caused significant multicellular tissue changes, including altered astrocyte responses and impaired functional recovery. This work reveals previously unknown ways in which proliferating NG2 cells contribute to endogenous repair after SCI.

NG2 cells (polydendrocytes) comprise an abundant glial population that is widely and uniformly distributed throughout the developing and mature CNS and are identified by the expression of the NG2 proteoglycan at the cell surface. Although recent electrophysiological studies suggest that they are capable of receiving signals from axon terminals, other studies, based on the finding that the NG2 molecule itself induces growth cone collapse, have led to a widely held speculation that NG2 cells themselves also repel and inhibit growing axons. In this study, we have examined the effects of rat NG2 cells on growing hippocampal and neocortical axons in vitro and in vivo. NG2 cells did not repel growing axons but promoted their growth in vitro, and axonal growth cones formed extensive contacts with NG2 cells both in vitro and in the developing corpus callosum. Punctate immunoreactivity for fibronectin and laminin was found to be colocalized with NG2 on the surface of NG2 cells. Altering the level of cell surface NG2 expression had no effect on the growth-promoting effects of NG2 cells on growing axons. Thus, our study indicates that NG2 cells are not inhibitory to growing axons but provide an adhesive substrate for axonal growth cones and promote their growth even in the presence of elevated levels of the NG2 proteoglycan. These findings suggest a novel role for NG2 cells in facilitating axonal growth during development and regeneration.

PIWI proteins, a subclade of the Argonaute family proteins, are expressed predominantly in the germline and bind to PIWI-interacting RNAs (piRNAs), which are 25–31 nucleotides in length. The PIWI/piRNA pathway plays critical roles in germline development by regulating transposons and other targets to maintain genome integrity. While the functions of PIWI in the germline have been extensively investigated, recent studies have accumulated evidence that the human PIWI proteins, HIWI and HILI, are aberrantly expressed in a variety of cancers. This review summarizes our knowledge of PIWI expression in cancer and discusses its possible role in tumorigenesis.

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