Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan.
Development. 2011 Aug;138(15):3159-68. doi: 10.1242/dev.062380. Epub 2011 Jun 29.
The transition from mitosis to meiosis is unique to germ cells. In murine embryonic ovaries and juvenile testes, retinoic acid (RA) induces meiosis via the stimulated by retinoic acid gene 8 (Stra8), but its molecular pathway requires elucidation. We present genetic evidence in vivo and in vitro that neuregulins (NRGs) are essential for the proliferation of spermatogonia and the initiation of meiosis. Tamoxifen (TAM) was injected into 14-day post-partum (dpp) Sertoli cell-specific conditional Nrg1(Ser-/-) mutant mice. TAM induced testis degeneration, suppressed BrdU incorporation into spermatogonia and pre-leptotene primary spermatocytes, and decreased and increased the number of STRA8-positive and TUNEL-positive cells, respectively. In testicular organ cultures from 5-6 dpp wild-type mice and cultures of their re-aggregated spermatogonia and Sertoli cells, FSH, RA [all-trans-retinoic acid (ATRA), AM580, 9-cis-RA] and NRG1 promoted spermatogonial proliferation and meiotic initiation. However, TAM treatment of testicular organ cultures from the Nrg1(Ser-/-) mutants suppressed spermatogonial proliferation and meiotic initiation that was promoted by FSH or AM580. In re-aggregated cultures of purified spermatogonia, NRG1, NRG3, ATRA and 9-cis-RA promoted their proliferation and meiotic initiation, but neither AM580 nor FSH did. In addition, FSH, RAs and NRG1 promoted Nrg1 and Nrg3 mRNA expression in Sertoli cells. These results indicate that in juvenile testes RA and FSH induced meiosis indirectly through Sertoli cells when NRG1 and NRG3 were upregulated, as NRG1 amplified itself and NRG3. The amplified NRG1 and NRG3 directly induced meiosis in spermatogonia. In addition, ATRA and 9-cis-RA activated spermatogonia directly and promoted their proliferation and eventually meiotic initiation.
有丝分裂向减数分裂的转变是生殖细胞所特有的。在鼠胚胎卵巢和幼年睾丸中，视黄酸（RA）通过视黄酸诱导基因 8（Stra8）诱导减数分裂，但它的分子途径需要阐明。我们体内和体外的遗传证据表明，神经调节蛋白（NRGs）是精原细胞增殖和减数分裂起始所必需的。他莫昔芬（TAM）被注射到产后 14 天（dpp）的 Sertoli 细胞特异性条件性 Nrg1（Ser-/-）突变小鼠中。TAM 诱导睾丸退化，抑制 BrdU 掺入精原细胞和早细线期初级精母细胞，并分别减少和增加 STRA8 阳性和 TUNEL 阳性细胞的数量。在来自 5-6 dpp 野生型小鼠的睾丸器官培养物中和它们重新聚集的精原细胞和 Sertoli 细胞的培养物中，FSH、RA[全反式视黄酸（ATRA）、AM580、9-顺式-RA]和 NRG1 促进精原细胞增殖和减数分裂起始。然而，TAM 处理 Nrg1（Ser-/-）突变体的睾丸器官培养物抑制了 FSH 或 AM580 促进的精原细胞增殖和减数分裂起始。在纯化的精原细胞的重新聚集培养物中，NRG1、NRG3、ATRA 和 9-顺式-RA 促进了它们的增殖和减数分裂起始，但 AM580 和 FSH 都没有。此外，FSH、RAs 和 NRG1 促进了 Sertoli 细胞中 Nrg1 和 Nrg3 mRNA 的表达。这些结果表明，在幼年睾丸中，当 NRG1 和 NRG3 上调时，RA 和 FSH 通过 Sertoli 细胞间接诱导减数分裂，因为 NRG1 自身扩增和 NRG3。扩增的 NRG1 和 NRG3 直接诱导精原细胞减数分裂。此外，ATRA 和 9-顺式-RA 直接激活精原细胞，并促进其增殖，最终诱导减数分裂起始。
