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Germ Cell-Specific Retinoic Acid Receptor ? Functions in Germ Cell Organization, Meiotic Integrity, and Spermatogonia.

ABSTRACT: Retinoic acid receptor ? (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.

SUBMITTER: Peer NR

PROVIDER: S-EPMC6112597 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Germ Cell-Specific Retinoic Acid Receptor α Functions in Germ Cell Organization, Meiotic Integrity, and Spermatogonia.

Peer Natalie R NR Law Sze Ming SM Murdoch Brenda B Goulding Eugenia H EH Eddy Edward M EM Kim Kwanhee K

Endocrinology 20180901 9

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 reduce ...[more]

PMID: 30099545

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Project description:BACKGROUND: Mammalian germ cells undergo meiosis to produce sperm or eggs, haploid cells that are primed to meet and propagate life. Meiosis is initiated by retinoic acid and meiotic prophase is the first and most complex stage of meiosis when homologous chromosomes pair to exchange genetic information. Errors in meiosis can lead to infertility and birth defects. However, despite the importance of this process, germ cell-specific gene expression patterns during meiosis remain undefined due to difficulty in obtaining pure germ cell samples, especially in females, where prophase occurs in the embryonic ovary. Indeed, mixed signals from both germ cells and somatic cells complicate gonadal transcriptome studies. RESULTS: We developed a machine-learning method for identifying germ cell-specific patterns of gene expression in microarray data from mammalian gonads, specifically during meiotic initiation and prophase. At 10% recall, the method detected spermatocyte genes and oocyte genes with 90% and 94% precision, respectively. Our method outperformed gonadal expression levels and gonadal expression correlations in predicting germ cell-specific expression. Top-predicted spermatocyte and oocyte genes were both preferentially localized to the X chromosome and significantly enriched for essential genes. Also identified were transcription factors and microRNAs that might regulate germ cell-specific expression. Finally, we experimentally validated Rps6ka3, a top-predicted X-linked spermatocyte gene. Protein localization studies in the mouse testis revealed germ cell-specific expression of RPS6KA3, mainly detected in the cytoplasm of spermatogonia and prophase spermatocytes. CONCLUSIONS: We have demonstrated that, through the use of machine-learning methods, it is possible to detect germ cell-specific expression from gonadal microarray data. Results from this study improve our understanding of the transition from germ cells to meiocytes in the mammalian gonad. Further, this approach is applicable to other tissues for which isolating cell populations remains difficult.

Dataset Information

Germ Cell-Specific Retinoic Acid Receptor ? Functions in Germ Cell Organization, Meiotic Integrity, and Spermatogonia.

Publications

Germ Cell-Specific Retinoic Acid Receptor α Functions in Germ Cell Organization, Meiotic Integrity, and Spermatogonia.

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