Genetic and Chemical Controls of Sperm Fate and Spermatocyte Dedifferentiation via PUF-8 and MPK-1 in Caenorhabditis elegans

卷:12

Article

关键词: GERMLINE STEM-CELLS;    MODEL SYSTEM;    PHOSPHATASE LIP-1;    SEX DETERMINATION;    LIFE-SPAN;    PUMILIO;    RNA;    BINDING;    PROTEIN;    PROLIFERATION;   

DOI  :  10.3390/cells12030434

来源: SCIE

【 摘 要 】

Using the nematode C. elegans germline as a model system, we previously reported that PUF-8 (a PUF RNA-binding protein) and LIP-1 (a dual-specificity phosphatase) repress sperm fate at 20 degrees C and the dedifferentiation of spermatocytes into mitotic cells (termed spermatocyte dedifferentiation) at 25 degrees C. Thus, double mutants lacking both PUF-8 and LIP-1 produce excess sperm at 20 degrees C, and their spermatocytes return to mitotically dividing cells via dedifferentiation at 25 degrees C, resulting in germline tumors. To gain insight into the molecular competence for spermatocyte dedifferentiation, we compared the germline phenotypes of three mutant strains that produce excess sperm-fem-3(q20gf), puf-8(q725); fem-3(q20gf), and puf-8(q725); lip-1(zh15). Spermatocyte dedifferentiation was not observed in fem-3(q20gf) mutants, but it was more severe in puf-8(q725); lip-1(zh15) than in puf-8(q725); fem-3(q20gf) mutants. These results suggest that MPK-1 (the C. elegans ERK1/2 MAPK ortholog) activation in the absence of PUF-8 is required to promote spermatocyte dedifferentiation. This idea was confirmed using Resveratrol (RSV), a potential activator of MPK-1 and ERK1/2 in C. elegans and human cells, respectively. Notably, spermatocyte dedifferentiation was significantly enhanced by RSV treatment in the absence of PUF-8, and its effect was blocked by mpk-1 RNAi. We, therefore, conclude that PUF-8 and MPK-1 are essential regulators for spermatocyte dedifferentiation and tumorigenesis. Since these regulators are broadly conserved, we suggest that similar regulatory circuitry may control cellular dedifferentiation and tumorigenesis in other organisms, including humans.