Abstract
Whether cell senescence is involved in the aging of neural precursor cells (NPCs) remains unknown, although it is obvious that the cells accumulate genetic mutations and lose their self-renewal capability (stem cell exhaustion) with age. Using a serum-induced mouse oligodendrocyte precursor cell (OPC) senescence model and DNA microarray, we identified esophageal cancer-related gene 4 (Ecrg4), which was originally found as a gene upregulated in non-tumor cells surrounding the tumor, with implications for the senescence-like state in the aging brain. We show that Ecrg4 is upregulated in senescent OPCs and that its overexpression in OPCs induces senescence by the acceleration of the proteasome-dependent degradation of Cyclins D1 and D3, whereas knockdown of Ecrg4 by a specific short hairpin RNA (shRNA) prevented these phenotypes. We demonstrate that senescent OPCs secrete Ecrg4 and that recombinant Ecrg4 induces OPC senescence in culture. Moreover, Ecrg4 expression increases in both OPCs and NPCs in aged brain, accompanied by the expression of senescence-associated beta-galactosidase activity, indicating the cells' entrance into senescence. These results suggest Ecrg4 is a novel factor linking neural-cell senescence and aging as well as tumorigenesis.
