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Deletion of the mouse X-linked Prame gene causes germ cell reduction in spermatogenesis.

小鼠 X 连锁 Prame 基因的缺失导致精子发生中的生殖细胞减少。

  • 影响因子:2.73
  • DOI:10.1002/mrd.23324
  • 作者列表:"Lu C","Yang M","Rossi RM","Wang A","Feitosa WB","Diaz FJ","Liu WS
  • 发表时间:2020-02-03
Abstract

:Preferentially expressed antigen in melanoma (PRAME) is cancer/testis antigen and a transcriptional repressor, inhibiting the signaling of retinoic acid through the retinoic acid receptor (RAR) for promoting cell proliferation and preventing cell apoptosis in cancer cells. The role of PRAME in testis and germline is unknown. We report here the generation and characterization of an X-linked Prame conditional knockout (cKO) mouse. Although fertile, the testis size (p < .01) and sperm count (p < .05) of the Prame cKO mice were significantly reduced by 12% at 4 months of age compared with the Prame floxed mice. Histological, immunofluorescence with germ cell-specific markers and terminal deoxynucleotidyl transferase dUTP nick end labeling analyses of testis cross-sections at postnatal day 7 (P7), P14, P21, P35, P120, and P365 indicated a significant increase in apoptotic germ cells at P7 and P14 and an increase in abnormal seminiferous tubules at P21 and P35. Germ cells were gradually lost resulting in two different phenotypes in the Prame cKO testes: Sertoli-cell-only for some of the affected tubules in young mice (at P35) and germ cell arrest at spermatogonia stage for other affected tubules in mature mice. Both phenotypes were a consequence of disruption in RAR signaling pathway by the depletion of Prame at a different time point during the first and subsequent rounds of spermatogenesis. The results suggest that Prame plays a minor, but important role in spermatogenesis and different paralogs in the Prame gene family may be functionally and partially redundant.

摘要

: 黑色素瘤中优先表达的抗原 (PRAME) 是癌症/睾丸抗原和转录抑制因子,通过视黄酸受体 (RAR) 抑制视黄酸的信号传导用于促进癌细胞的细胞增殖和防止细胞凋亡。PRAME 在睾丸和生殖系中的作用尚不清楚。我们在这里报告了 X 连锁 Prame 条件性敲除 (cKO) 小鼠的产生和表征。虽然有生育能力,但睾丸大小 (p <.01) 和精子数量 (p <.05) 与 Prame floxed 小鼠相比,Prame cKO 小鼠在 4 月龄时显著减少了 12%。出生后第 7 天 (P7) 、 P14 、 P21 、 P35 、 P120 、睾丸横断面的组织学、生殖细胞特异性标记和末端脱氧核苷酸转移酶 (dUTP) 缺口末端标记免疫荧光分析 p365 表示 P7 和 P14 时凋亡生殖细胞显著增加,P21 和 p35 时异常生精小管显著增加。生殖细胞逐渐丢失,导致 Prame cKO 睾丸出现两种不同的表型: Sertoli-细胞-仅适用于年轻小鼠的一些受影响的小管 (P35) 和成熟小鼠其他受累小管在精原细胞阶段的生殖细胞阻滞。这两种表型都是在精子发生的第一轮和随后几轮过程中,Prame 在不同时间点被耗竭而破坏 RAR 信号通路的结果。结果表明,Prame 在精子发生中起着次要但重要的作用,Prame 基因家族中的不同副染色体可能具有功能和部分冗余。

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