Genetic and Chemical Controls of Sperm Fate and Spermatocyte Dedifferentiation via PUF-8 and MPK-1 in Caenorhabditis elegans.
Genetic and Chemical Controls of Sperm Fate and Spermatocyte Dedifferentiation via PUF-8 and MPK-1 in Caenorhabditis elegans.
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利用线虫C.以线虫生殖系为模型系统，我们先前报道了PUF-8（一种PUF RNA结合蛋白）和LIP-1（一种双特异性磷酸酶）在20 °C下抑制精子命运，在25 °C下抑制精母细胞向有丝分裂细胞的去分化（称为“精母细胞去分化”）。因此，缺乏PUF-8和LIP-1的双突变体在20 °C下产生过量的精子，并且它们的精母细胞在25 °C下通过去分化返回到有丝分裂细胞，导致生殖系肿瘤。为了深入了解精母细胞去分化的分子能力，我们比较了三种产生过量精子的突变株fem-3（q20 gf）、puf-8（q725）; fem-3（q20 gf）和puf-8（q725）; lip-1（zh 15）的种系表型。在fem-3（q20 gf）突变体中未观察到精母细胞去分化，但在puf-8（q725）; lip-1（zh 15）中比puf-8（q725）; fem-3（q20 gf）突变体中更严重。提示MPK-1（C. elegans ERK 1/2 MAPK直系同源物）活化是促进精母细胞去分化所必需的。白藜芦醇（Resveratrol，RSV）是一种潜在的MPK-1和ERK 1/2激活剂，在C. elegans线虫and human人cells细胞，either分别.值得注意的是，在不存在PUF-8的情况下，RSV处理显著增强了精母细胞去分化，并且其作用被mpk-1 RNAi阻断。因此，我们得出结论，PUF-8和MPK-1是精母细胞去分化和肿瘤发生的重要调节因子。由于这些监管机构是广泛保守的，我们认为，类似的调节电路可能控制细胞去分化和肿瘤发生在其他生物体，包括人类。
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 °C and the dedifferentiation of spermatocytes into mitotic cells (termed “spermatocyte dedifferentiation”) at 25 °C. Thus, double mutants lacking both PUF-8 and LIP-1 produce excess sperm at 20 °C, and their spermatocytes return to mitotically dividing cells via dedifferentiation at 25 °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.
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