Targeted Inactivation of Testicular Nuclear Orphan Receptor 4 Delays and Disrupts Late Meiotic Prophase and Subsequent Meiotic Divisions of Spermatogenesis

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Abstract
Testicular orphan nuclear receptor 4 (TR4) is specifically and stage-dependently expressed in late-stage pachytene spermatocytes and round spermatids. In the developing mouse testis, the highest expression of TR4 can be detected at postnatal days 16 to 21 when the first wave of spermatogenesis progresses to late meiotic prophase. Using a knockout strategy to delete TR4 in mice, we found that sperm production in TR4−/− mice is reduced. The comparison of testes from developing TR4+/+ and TR4−/− mice shows that spermatogenesis in TR4−/− mice is delayed. Analysis of the first wave of spermatogenesis shows that the delay can be due to delay and disruption of spermatogenesis at the end of late meiotic prophase and subsequent meiotic divisions. Seminiferous tubule staging shows that stages X to XII, where late meiotic prophase and meiotic divisions take place, are delayed and disrupted in TR4−/− mice. Histological examination of testis sections from TR4−/− mice shows degenerated primary spermatocytes and some necrotic tubules. Testis-specific gene analyses show that the expression of sperm 1 and cyclin A1, which are genes expressed at the end of meiotic prophase, was delayed and decreased in TR4−/− mouse testes. Taken together, results from TR4+/+ and TR4−/− mice indicate that TR4 is essential for normal spermatogenesis in mice.