Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice.
Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice.
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DOI：
10.1242/dmm.008649
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发表时间：
2012-11
影响因子：
4.3
通讯作者：
Brehm R
中科院分区：
文献类型：
--
作者：
Giese S;Hossain H;Markmann M;Chakraborty T;Tchatalbachev S;Guillou F;Bergmann M;Failing K;Weider K;Brehm R
过去 20 年来，已有报道称人类男性生殖功能显着下降，但其分子机制仍知之甚少。然而，最近的研究表明间隙连接蛋白 connexin-43（CX43；也称为 GJA1）可能参与其中。 CX43 是大多数物种（包括人类）中主要的睾丸连接蛋白 (CX)。其表达的改变与不同形式的生精障碍和不孕症有关。精子发生受损的男性通常会表现出生殖细胞 (GC) 和支持细胞 (SC) 中 CX43 表达的减少或缺失。 SC (SCCx43KO) 中 Gja1 基因条件性敲除 (KO) 的成年雄性转基因小鼠 (SCCx43KO) 显示出与人类相当的睾丸表型，并且不育。为了检测导致成年 SCCx43KO 小鼠睾丸表型及其无法启动精子发生的可能信号通路和分子机制，我们比较了 8 日龄 SCCx43KO 和野生型 (WT) 小鼠的睾丸基因表达。微阵列分析显示，SCCx43KO 小鼠睾丸中有 658 个基因受到显着调控。在这些基因中，135 个基因上调，而 523 个基因下调。对于选定的基因，使用定量实时 PCR 和免疫染色证实了微阵列分析的结果。大多数下调基因是 GC 特异性的，对于精子发生的有丝分裂和减数分裂进程至关重要，包括 Stra8、Dazl 和 DM（dsx 和 map-3）基因家族的成员。其他改变的基因可能与转录、代谢、细胞迁移和细胞骨架组织有关。我们的数据表明，SC 中 Cx43 的缺失会导致青春期前小鼠基因表达的多重改变，并且主要影响 GC。候选基因可以为研究人员探索显示相应生精缺陷的患者的人类睾丸活检以及研究人类男性不育的分子机制提供有用的标记。
A significant decline in human male reproductive function has been reported for the past 20 years but the molecular mechanisms remain poorly understood. However, recent studies showed that the gap junction protein connexin-43 (CX43; also known as GJA1) might be involved. CX43 is the predominant testicular connexin (CX) in most species, including in humans. Alterations of its expression are associated with different forms of spermatogenic disorders and infertility. Men with impaired spermatogenesis often exhibit a reduction or loss of CX43 expression in germ cells (GCs) and Sertoli cells (SCs). Adult male transgenic mice with a conditional knockout (KO) of the Gja1 gene [referred to here as connexin-43 (Cx43)] in SCs (SCCx43KO) show a comparable testicular phenotype to humans and are infertile. To detect possible signaling pathways and molecular mechanisms leading to the testicular phenotype in adult SCCx43KO mice and to their failure to initiate spermatogenesis, the testicular gene expression of 8-day-old SCCx43KO and wild-type (WT) mice was compared. Microarray analysis revealed that 658 genes were significantly regulated in testes of SCCx43KO mice. Of these genes, 135 were upregulated, whereas 523 genes were downregulated. For selected genes the results of the microarray analysis were confirmed using quantitative real-time PCR and immunostaining. The majority of the downregulated genes are GC-specific and are essential for mitotic and meiotic progression of spermatogenesis, including Stra8, Dazl and members of the DM (dsx and map-3) gene family. Other altered genes can be associated with transcription, metabolism, cell migration and cytoskeleton organization. Our data show that deletion of Cx43 in SCs leads to multiple alterations of gene expression in prepubertal mice and primarily affects GCs. The candidate genes could represent helpful markers for investigators exploring human testicular biopsies from patients showing corresponding spermatogenic deficiencies and for studying the molecular mechanisms of human male sterility.
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DOI：
10.1142/s0219720005001442
发表时间：
2005-10-01
影响因子：
1
作者：
Breitling, Rainer;Herzyk, Pawel
通讯作者：
Herzyk, Pawel
影响因子：
5
作者：
Defamie, N;Berthaut, I;Pointis, G
通讯作者：
Pointis, G
极性蛋白和肌动蛋白调节蛋白是在精子发生过程中调节细胞上皮细胞粘附的不可能的伴侣。
影响因子：
2
作者：
Cheng CY;Wong EW;Lie PP;Mruk DD;Xiao X;Li MW;Lui WY;Lee WM
通讯作者：
Lee WM
影响因子：
10.5
作者：
Dai, X;Schonbaum, C;Fuchs, E
通讯作者：
Fuchs, E
影响因子：
2.7
作者：
Carette, Diane;Weider, Karola;Pointis, Georges
通讯作者：
Pointis, Georges