MAP3K4 kinase activity dependent control of mouse gonadal sex determination†.
MAP3K4 kinase activity dependent control of mouse gonadal sex determination†.
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MAP3K4 激酶活性依赖性控制小鼠性腺性别决定。
DOI：
10.1093/biolre/ioab083
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发表时间：
2021
影响因子：
3.6
通讯作者：
Abell,AmyN
中科院分区：
文献类型：
--
作者：
Shendy,NohaAM;Broadhurst,AmberL;Shoemaker,Kristin;Read,Robert;Abell,AmyN
性别决定需要双能性腺对睾丸或卵巢的命运的承诺。激酶Map 3 k4基因缺失导致XY小鼠性腺性逆转，转基因表达Map 3 k4可挽救性逆转表型。Map 3 k4编码一个大的、多功能的蛋白质，具有一个激酶结构域和几个额外的蛋白质-蛋白质相互作用结构域。尽管MAP 3 K4在雄性性腺性别决定中发挥着关键作用，但尚不清楚是否需要MAP 3 K4的激酶活性。在这里，我们使用小鼠表达全长，激酶失活的MAP 3 K4从内源性Map 3 k4基因座检查MAP 3 K4激酶活性在性别决定的要求。虽然纯合子激酶失活的MAP 3 K4（Map 3 k4 KI/KI）是致命的，一小部分存活到成年。我们发现，Map 3 k4 KI/KI成人表现出4：1的女性偏向的性别比例。许多成年Map 3 k4 KI/KI表型女性具有Y染色体。XYMap 3 k4 KI/KI性反转成虫表现雌性交配行为，但不产生后代。生殖器官明显是女性的，但卵巢表型有很宽的范围，包括卵巢缺失、原始卵巢、卵巢尺寸缩小以及在所有发育阶段都有卵泡的卵巢。此外，XYMap 3 k4 KI/KI成年小鼠比雄性或雌性Map 3 k4 WT/WT小鼠小。对E11.5性腺性别决定关键期的研究表明，在XYMap 3 k4 KI/KI胚胎中，MAP 3 K4激酶活性的丧失导致Sry表达的丧失，表明胚胎雄性性腺性逆转。总之，这些研究结果表明，激酶活性的MAP 3 K4在男性性腺性别决定的重要作用。
Sex determination requires the commitment of bipotential gonads to either a testis or an ovarian fate. Gene deletion of the kinaseMap3k4results in gonadal sex reversal in XY mice, and transgenic re-expression ofMap3k4rescues the sex reversal phenotype.Map3k4encodes a large, multi-functional protein possessing a kinase domain and several, additional protein–protein interaction domains. Although MAP3K4 plays a critical role in male gonadal sex determination, it is unknown if the kinase activity of MAP3K4 is required. Here, we use mice expressing full-length, kinase-inactive MAP3K4 from the endogenousMap3k4locus to examine the requirement of MAP3K4 kinase activity in sex determination. Although homozygous kinase-inactivation of MAP3K4 (Map3k4KI/KI) is lethal, a small fraction survive to adulthood. We showMap3k4KI/KIadults exhibit a 4:1 female-biased sex ratio. Many adultMap3k4KI/KIphenotypic females have a Y chromosome. XYMap3k4KI/KIadults with sex reversal display female mating behavior, but do not give rise to offspring. Reproductive organs are overtly female, but there is a broad spectrum of ovarian phenotypes, including ovarian absence, primitive ovaries, reduced ovarian size, and ovaries having follicles in all stages of development. Further, XYMap3k4KI/KIadults are smaller than either male or femaleMap3k4WT/WTmice. Examination of the critical stage of gonadal sex determination at E11.5 shows that loss of MAP3K4 kinase activity results in the loss ofSryexpression in XYMap3k4KI/KIembryos, indicating embryonic male gonadal sex reversal. Together, these findings demonstrate the essential role for kinase activity of MAP3K4 in male gonadal sex determination.