title: Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1.
abstract: In mammals, the Y chromosome is a dominant male determinant, causing the bipotential gonad to develop as a testis. Recently, cases of familial and spontaneous 46,XY disorders of sex development (DSD) have been attributed to mutations in the human gene encoding mitogen-activated protein kinase kinase kinase 1, MAP3K1, a component of the mitogen-activated protein kinase (MAPK) signal transduction pathway. In individuals harbouring heterozygous mutations in MAP3K1, dysregulation of MAPK signalling was observed in lymphoblastoid cell lines, suggesting a causal role for these mutations in disrupting XY sexual development. Mice lacking the cognate gene, Map3k1, are viable and exhibit the eyes open at birth (EOB) phenotype on a mixed genetic background, but on the C57BL/6J genetic background most mice die at around 14.5 dpc due to a failure of erythropoiesis in the fetal liver. However, no systematic examination of sexual development in Map3k1-deficient mice has been described, an omission that is especially relevant in the case of C57BL/6J, a genetic background that is sensitized to disruptions to testis determination. Here, we report that on a mixed genetic background mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development. On C57BL/6J, significant non-viability is observed with very few animals surviving to adulthood. However, an examination of development in Map3k1-deficient XY embryos on this genetic background revealed no significant defects in testis determination, although minor abnormalities were observed, including an increase in gonadal length. Based on these observations, we conclude that MAP3K1 is not required for mouse testis determination. We discuss the significance of these data for the functional interpretation of sex-reversing MAP3K1 mutations in humans.
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Warr
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.forename: Pam
authors.initials: P
authors.lastname: Siggers
authors.forename: Rachel
authors.initials: R
authors.lastname: Brixey
authors.forename: Hilda
authors.initials: H
authors.lastname: Tateossian
authors.forename: Asha
authors.initials: A
authors.lastname: Dopplapudi
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Andy
authors.initials: A
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D012734:Disorders of Sex Development / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006720:Homozygote; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D012733:Sex Differentiation / Q000235:genetics; D013737:Testis / Q000002:abnormalities* / Q000196:embryology; D013997:Time Factors
chemical_list: D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse