A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis
A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis
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DOI：
10.1073/pnas.0308114100
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发表时间：
2004-02-03
影响因子：
11.1
通讯作者：
Verhoeven, G
中科院分区：
文献类型：
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作者：
De Gendt, K;Swinnen, JV;Verhoeven, G
雄激素控制精子发生，但生殖细胞本身不表达功能性雄激素受体（AR）。雄激素调节被认为是由支持细胞和管周肌样细胞介导的，但它们的相对作用和所涉及的机制仍然很大程度上未知。使用Cre/IoxP技术，我们已经产生了具有普遍存在的AR敲除的小鼠以及仅在支持细胞（SC）中具有选择性AR敲除的小鼠。将AR基因的具有floxed外显子2的小鼠与在SC中普遍或选择性表达Cre重组酶的小鼠杂交（在抗苗勒管激素基因启动子的控制下）。AR基因敲除的雄性显示出完全的雄激素不敏感表型。睾丸位于腹部，生殖细胞发育严重中断。相比之下，SC AR敲除雄性显示正常的睾丸下降和雄性泌尿生殖道的发育。雄激素在SC中调控的同源异型盒基因Pem的表达严重下降。睾丸重量降低至WT同窝仔的28%。体视学分析表明，SC的数量没有变化，而精母细胞、圆形精子细胞和细长精子细胞的数量分别减少到WT的64%、3%和0%。这些变化与生殖细胞凋亡增加和晚期精母细胞或精子特异性基因表达显著减少有关。发展它的结论是，在SC中的AR的细胞自主行动是雄激素维持完整的精子发生的绝对要求，精母细胞/精子细胞的发育/生存严重依赖于雄激素。
Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/IoxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Mullerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatic! development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/ survival critically depends on androgens.