Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1.
Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1.
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DOI：
10.1172/jci12589
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发表时间：
2002-05
期刊：
影响因子：
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通讯作者：
R. Firestein;P. L. Nagy;M. Daly;P. Huie;M. Conti;M. Cleary
中科院分区：
文献类型：
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作者：
R. Firestein;P. L. Nagy;M. Daly;P. Huie;M. Conti;M. Cleary
假磷酸酶显示出与磷酸酶广泛的序列相似性，但在其活性位点共有基序中具有氨基酸改变，使其无催化活性。已经提出了在底物捕获或对接中的潜在作用，但在发育和分化过程中对假磷酸酶的具体要求尚不清楚。我们在这里证明，Sbf1，一个假磷酸酶的myotubularin家庭，表达在高水平的睾丸曲细精管，特别是在支持细胞，精原细胞，粗线期精母细胞，但不是在减数分裂后的圆形精子细胞。Sbf1基因缺失的小鼠表现出以无精子症为特征的雄性不育。生精缺陷发生在出生后17天的精子发生的第一波中，在粗线期精母细胞向单倍体精子细胞的同步进展过程中。Sertoli细胞的变性是最早观察到的表型，随后是精子细胞形成减少和老年小鼠生殖细胞区室的最终耗竭。在减数分裂前的生殖细胞和支持细胞中Sbf1的高水平表达结合的nullizyzygene表型与Sbf1在从二倍体到单倍体精母细胞的过渡中的关键作用一致。这些研究表明，一个pseudophosphatase的重要作用，并牵连的精子发生和生殖细胞分化的肌管蛋白家族蛋白调节的信号通路。
Pseudophosphatases display extensive sequence similarities to phosphatases but harbor amino acid alterations in their active-site consensus motifs that render them catalytically inactive. A potential role in substrate trapping or docking has been proposed, but the specific requirements for pseudophosphatases during development and differentiation are unknown. We demonstrate here that Sbf1, a pseudophosphatase of the myotubularin family, is expressed at high levels in seminiferous tubules of the testis, specifically in Sertoli's cells, spermatogonia, and pachytene spermatocytes, but not in postmeiotic round spermatids. Mice that are nullizygous for Sbf1 exhibit male infertility characterized by azoospermia. The onset of the spermatogenic defect occurs in the first wave of spermatogenesis at 17 days after birth during the synchronized progression of pachytene spermatocytes to haploid spermatids. Vacuolation of the Sertoli's cells is the earliest observed phenotype and is followed by reduced formation of spermatids and eventual depletion of the germ cell compartment in older mice. The nullizygous phenotype in conjunction with high-level expression of Sbf1 in premeiotic germ cells and Sertoli's cells is consistent with a crucial role for Sbf1 in transition from diploid to haploid spermatocytes. These studies demonstrate an essential role for a pseudophosphatase and implicate signaling pathways regulated by myotubularin family proteins in spermatogenesis and germ cell differentiation.