MAP3K4 kinase activity dependent control of mouse gonadal sex determination†.

Autor:	Shendy NAM; Department of Biological Sciences, University of Memphis, Memphis, TN, USA.; Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt., Broadhurst AL; Department of Biological Sciences, University of Memphis, Memphis, TN, USA., Shoemaker K; Department of Biological Sciences, University of Memphis, Memphis, TN, USA., Read R; Department of Biological Sciences, University of Memphis, Memphis, TN, USA., Abell AN; Department of Biological Sciences, University of Memphis, Memphis, TN, USA.
Jazyk:	angličtina
Zdroj:	Biology of reproduction [Biol Reprod] 2021 Aug 03; Vol. 105 (2), pp. 491-502.
DOI:	10.1093/biolre/ioab083
Abstrakt:	Sex determination requires the commitment of bipotential gonads to either a testis or an ovarian fate. Gene deletion of the kinase Map3k4 results in gonadal sex reversal in XY mice, and transgenic re-expression of Map3k4 rescues the sex reversal phenotype. Map3k4 encodes 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 endogenous Map3k4 locus 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 show Map3k4KI/KI adults exhibit a 4:1 female-biased sex ratio. Many adult Map3k4KI/KI phenotypic females have a Y chromosome. XY Map3k4KI/KI adults 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, XY Map3k4KI/KI adults are smaller than either male or female Map3k4WT/WT mice. Examination of the critical stage of gonadal sex determination at E11.5 shows that loss of MAP3K4 kinase activity results in the loss of Sry expression in XY Map3k4KI/KI embryos, indicating embryonic male gonadal sex reversal. Together, these findings demonstrate the essential role for kinase activity of MAP3K4 in male gonadal sex determination. (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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