School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, Washington.
Department of Animal and Veterinary Science, University of Idaho, Moscow, Idaho.
Endocrinology. 2018 Sep 1;159(9):3403-3420. doi: 10.1210/en.2018-00533.
Retinoic acid receptor α (RARA), a retinoic acid-dependent transcription factor, is expressed in both somatic and germ cells of the testis. Rara-null male mice with global Rara mutations displayed severely degenerated testis and infertility phenotypes. To elucidate the specific responsibility of germ cell RARA in spermatogenesis, Rara was deleted in germ cells, generating germ cell-specific Rara conditional knockout (cKO) mice. These Rara cKO animals exhibited phenotypes of quantitatively reduced epididymal sperm counts and disorganized germ cell layers in the seminiferous tubules, which worsened with aging. Abnormal tubules lacked lumen, contained vacuoles, and showed massive germ cell sloughing, all characteristics similar to those observed in Rara-null tubules. Spermatocyte chromosomal spreads revealed a novel role for germ cell RARA in modulating the integrity of synaptonemal complexes and meiotic progression. Furthermore, the initiation of spermatogenesis from spermatogonial stem cells was decreased in Rara cKO testes following busulfan treatment, supporting a role of germ cell RARA in spermatogonial proliferation. Collectively, the evidence in this study indicates that RARA produced in male germ cells has a broad spectrum of functions throughout spermatogenesis, which includes the maintenance of seminiferous epithelium organization, the integrity of the meiotic genome, and spermatogonial proliferation and differentiation. The results further suggest that germ cell RARA has dual functions: intrinsically in germ cells, balancing proliferation and differentiation of spermatogonia, and controlling genome integrity during meiosis; and extrinsically in the crosstalks with Sertoli cells, controlling the cell junctional physiology for coordinating proper spatial and temporal development of germ cells during spermatogenesis.
视黄酸受体 α（RARA）是一种依赖视黄酸的转录因子，在睾丸的体细胞和生殖细胞中均有表达。具有全局 Rara 突变的 Rara 缺失雄性小鼠表现出严重退化的睾丸和不育表型。为了阐明生殖细胞 RARA 在精子发生中的特定责任，我们在生殖细胞中删除了 Rara，产生了生殖细胞特异性 Rara 条件性敲除（cKO）小鼠。这些 Rara cKO 动物表现出附睾精子计数明显减少和精小管中生殖细胞层排列紊乱的表型，随着年龄的增长而恶化。异常的小管缺乏腔，含有空泡，并显示大量生殖细胞脱落，所有这些特征都类似于在 Rara 缺失小管中观察到的特征。精母细胞染色体铺片揭示了生殖细胞 RARA 在调节联会复合体完整性和减数分裂进程中的新作用。此外，在博舒替尼处理后，Rara cKO 睾丸中从精原干细胞开始的精子发生起始减少，支持生殖细胞 RARA 在精原细胞增殖中的作用。总之，本研究中的证据表明，雄性生殖细胞中产生的 RARA 在整个精子发生过程中具有广泛的功能，包括维持生精上皮组织的结构、减数分裂基因组的完整性以及精原细胞的增殖和分化。结果进一步表明，生殖细胞 RARA 具有双重功能：内在地在生殖细胞中，平衡精原细胞的增殖和分化，以及控制减数分裂过程中的基因组完整性；外在地与支持细胞的相互作用，控制细胞连接生理学，以协调精子发生过程中生殖细胞的适当时空发育。
