title: Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination.
abstract: Testis determination in mammals is initiated by expression of SRY in somatic cells of the embryonic gonad. Genetic analyses in the mouse have revealed a requirement for mitogen-activated protein kinase (MAPK) signaling in testis determination: targeted loss of the kinases MAP3K4 and p38 MAPK causes complete XY embryonic gonadal sex reversal. These kinases occupy positions at the top and bottom level, respectively, in the canonical three-tier MAPK-signaling cascade: MAP3K, MAP2K, MAPK. To date, no role in sex determination has been attributed to a MAP2K, although such a function is predicted to exist. Here, we report roles for the kinases MAP2K3 and MAP2K6 in testis determination. C57BL/6J (B6) embryos lacking MAP2K3 exhibited no significant abnormalities of testis development, whilst those lacking MAP2K6 exhibited a minor delay in testis determination. Compound mutants lacking three out of four functional alleles at the two loci also exhibited delayed testis determination and transient ovotestis formation as a consequence, suggestive of partially redundant roles for these kinases in testis determination. Early lethality of double-knockout embryos precludes analysis of sexual development. To reveal their roles in testis determination more clearly, we generated Map2k mutant B6 embryos using a weaker Sry allele (Sry(AKR)). Loss of Map2k3 on this highly sensitized background exacerbates ovotestis development, whilst loss of Map2k6 results in complete XY gonadal sex reversal associated with reduction of Sry expression at 11.25 days postcoitum. Our data suggest that MAP2K6 functions in mouse testis determination, via positive effects on Sry, and also indicate a minor role for MAP2K3.
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Warr
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
authors.forename: Pam
authors.initials: P
authors.lastname: Siggers
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
authors.forename: Gwenn-Aël
authors.initials: GA
authors.lastname: Carré
authors.affiliation: The Mary Lyon Centre, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom a.greenfield@har.mrc.ac.uk.
authors.forename: Andy
authors.initials: A
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000502:physiology*; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019849:Sex Determination Processes / Q000235:genetics*; D012733:Sex Differentiation / Q000235:genetics; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000196:embryology* / Q000378:metabolism
chemical_list: D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse
keywords: MAP2K; MAP2K3; MAP2K6; MAP3K4; MAPK signaling; disorders of sex development (DSD); mouse genetics; mouse models; p38 MAPK; sex determination; sex reversal; testis development