Isoform-specific requirement for GSK3α in sperm for male fertility
Isoform-specific requirement for GSK3α in sperm for male fertility
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DOI：
10.1093/biolre/ioy020
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发表时间：
2018-08-01
影响因子：
3.6
通讯作者：
Vijayaraghavan, Srinivasan
中科院分区：
文献类型：
--
作者：
Bhattacharjee, Rahul;Goswami, Suranjana;Vijayaraghavan, Srinivasan
糖原合成酶激酶3 （GSK3）是一种高度保守的调节关键细胞功能的蛋白激酶。它的两个同工型，GSK3 α和GSK3 β，由不同的基因编码。在大多数组织中，这两种异构体在功能上是可互换的，除了在发育中的胚胎中，GSK3 β是必不可少的。两种同工异构体中任何一种的一个功能等位基因都足以维持正常的组织功能。这两种GSK3亚型存在于包括人类在内的几个物种的精子中，被认为在精子运动的附睾起始中起作用。使用遗传学方法，我们已经测试了睾丸和精子中两种GSK3亚型的需求。两种GSK3亚型在精子发生时均高水平表达。在发育中的小鼠睾丸生殖细胞中，有条件地敲除GSK3 α，但不敲除GSK3 β，会导致男性不育。缺乏GSK3 α和GSK3 β等位基因的小鼠是可育的。尽管在分化精子中表达和定位重叠，但GSK3 β并不能替代GSK3 α。GSK3 α缺失会损害精子己糖激酶活性，导致ATP水平降低。缺乏GSK3 α的尾端精子的净腺嘌呤核苷酸水平类似于未成熟的附睾精子。在缺乏GSK3 α的精子中，附睾精子成熟过程中发生的蛋白磷酸酶PP1 γ 2与其蛋白相互作用物的关联变化受到损害。GSK3的异构体特异性要求可能是由于其在精子主片段中的特定结合伙伴。睾丸和精子对正常功能和男性生育能力的GSK3 α的特殊需求是独一无二的。精子中的egsk3 α对男性生育能力至关重要。
Glycogen synthase kinase 3 (GSK3) is a highly conserved protein kinase regulating key cellular functions. Its two isoforms, GSK3 alpha and GSK3 beta, are encoded by distinct genes. In most tissues the two isoforms are functionally interchangeable, except in the developing embryo where GSK3 beta is essential. One functional allele of either of the two isoforms is sufficient to maintain normal tissue functions. Both GSK3 isoforms, present in sperm from several species including human, are suggested to play a role in epididymal initiation of sperm motility. Using genetic approaches, we have tested requirement for each of the two GSK3 isoforms in testis and sperm. Both GSK3 isoforms are expressed at high levels during the onset of spermatogenesis. Conditional knockout of GSK3 alpha, but not GSK3 beta, in developing testicular germ cells in mice results in male infertility. Mice lacking one allele each of GSK3 alpha and GSK3 beta are fertile. Despite overlapping expression and localization in differentiating spermatids, GSK3 beta does not substitute for GSK3 alpha. Loss of GSK3 alpha impairs sperm hexokinase activity resulting in low ATP levels. Net adenine nucleotide levels in caudal sperm lacking GSK3 alpha resemble immature caput epididymal sperm. Changes in the association of the protein phosphatase PP1 gamma 2 with its protein interactors occurring during epididymal sperm maturation is impaired in sperm lacking GSK3 alpha. The isoform-specific requirement for GSK3 is likely due to its specific binding partners in the sperm principal piece. Testis and sperm are unique in their specific requirement of GSK3 alpha for normal function and male fertility.Summary SentenceGSK3 alpha in sperm is essential for male fertility.