Selective Ablation of Ppp1cc Gene in Testicular Germ Cells Causes Oligo-Teratozoospermia and Infertility in Mice
Selective Ablation of Ppp1cc Gene in Testicular Germ Cells Causes Oligo-Teratozoospermia and Infertility in Mice
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DOI：
10.1095/biolreprod.113.110239
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发表时间：
2013-11-01
影响因子：
3.6
通讯作者：
Vijayaraghavan, Srinivasan
中科院分区：
文献类型：
--
作者：
Sinha, Nilam;Puri, Pawan;Vijayaraghavan, Srinivasan
丝氨酸/苏氨酸磷蛋白磷酸酶 1 (PP1) 的四种亚型源自三个基因，是已知最保守的蛋白质之一。 Ppp1cc 基因编码两个选择性剪接变体：PP1 gamma1 (PPP1CC1) 和 PP1 gamma2 (PPP1CC2)。 Ppp1cc 基因的整体缺失会导致两种同工型的丢失，并因精子发生受损而导致男性不育。这种表型被认为是由于睾丸中丰富的 PPP1CC2 缺失所致。虽然 PPP1CC2 占主导地位，但其他 PP1 亚型也在睾丸中表达。鉴于四种 PP1 同工型之间具有显着的同源性，其他 PP1 同工型缺乏对仅在睾丸中的一种 PP1 同工型的损失的补偿，这是令人惊讶的。在这里，我们首次记录了 PP1 同工型在出生后发育和成年小鼠睾丸中的表达模式。 PPP1CC1和PPP1CC2在睾丸中的表达时间和位点不重叠。 PPP1CC2 是四种 PP1 同工型中唯一未在支持细胞和精原细胞中检测到的一种。相反，PPP1CC2 可能是减数分裂后生殖细胞中唯一表达的 PP1 亚型。在Stra8启动子驱动的Cre转基因小鼠中，在分化的精原细胞发育阶段及之后的生殖细胞中删除Ppp1cc基因会导致少畸弱精子症和男性不育症，从而对全球Ppp1cc无效（-/-）小鼠进行表型复制。总而言之，这些结果证实，在全球 Ppp1cc 敲除小鼠和睾丸中表达低水平 PPP1CC2 的小鼠中观察到的生精缺陷是由于 PPP1CC2 在减数分裂和减数分裂后生殖细胞中的功能受损所致。
The four isoforms of serine/threonine phosphoprotein phosphatase 1 (PP1), derived from three genes, are among the most conserved proteins known. The Ppp1cc gene encodes two alternatively spliced variants, PP1 gamma1 (PPP1CC1) and PP1 gamma2 (PPP1CC2). Global deletion of the Ppp1cc gene, which causes loss of both isoforms, results in male infertility due to impaired spermatogenesis. This phenotype was assumed to be due to the loss of PPP1CC2, which is abundant in testis. While PPP1CC2 is predominant, other PP1 isoforms are also expressed in testis. Given the significant homology between the four PP1 isoforms, the lack of compensation by the other PP1 isoforms for loss of one, only in testis, is surprising. Here we document, for the first time, expression patterns of the PP1 isoforms in postnatal developing and adult mouse testis. The timing and sites of testis expression of PPP1CC1 and PPP1CC2 in testis are nonoverlapping. PPP1CC2 is the only one of the four PP1 isoforms not detected in sertoli cells and spermatogonia. Conversely, PPP1CC2 may be the only PP1 isoform expressed in postmeiotic germ cells. Deletion of the Ppp1cc gene in germ cells at the differentiated spermatogonia stage of development and beyond in Stra8 promoter-driven Cre transgenic mice results in oligo-terato-asthenozoospermia and male infertility, thus phenocopying global Ppp1cc null (-/-) mice. Taken together, these results confirm that spermatogenic defects observed in the global Ppp1cc knockout mice and in mice expressing low levels of PPP1CC2 in testis are due to compromised functions of PPP1CC2 in meiotic and postmeiotic germ cells.