title: The Leydig cell MEK/ERK pathway is critical for maintaining a functional population of adult Leydig cells and for fertility.
abstract: MAPK kinase (MEK)1 and MEK2 were deleted from Leydig cells by crossing Mek1(f/f);Mek2(-/-) and Cyp17iCre mice. Primary cultures of Leydig cell from mice of the appropriate genotype (Mek1(f/f);Mek2(-/-);iCre(+)) show decreased, but still detectable, MEK1 expression and decreased or absent ERK1/2 phosphorylation when stimulated with epidermal growth factor, Kit ligand, cAMP, or human choriogonadotropin (hCG). The body or testicular weights of Mek1(f/f);Mek2(-/-);iCre(+) mice are not significantly affected, but the testis have fewer Leydig cells. The Leydig cell hypoplasia is paralleled by decreased testicular expression of several Leydig cell markers, such as the lutropin receptor, steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, 17α-hydroxylase, and estrogen sulfotransferase. The expression of Sertoli or germ cell markers, as well as the shape, size, and cellular composition of the seminiferous tubules, are not affected. cAMP accumulation in response to hCG stimulation in primary cultures of Leydig cells from Mek1(f/f);Mek2(-/-);iCre(+) mice is normal, but basal testosterone and testosterone syntheses provoked by addition of hCG or a cAMP analog, or by addition of substrates such as 22-hydroxycholesterol or pregnenolone, are barely detectable. The Mek1(f/f);Mek2(-/-);iCre(+) males show decreased intratesticular testosterone and display several signs of hypoandrogenemia, such as elevated serum LH, decreased expression of two renal androgen-responsive genes, and decreased seminal vesicle weight. Also, in spite of normal sperm number and motility, the Mek1(f/f);Mek2(-/-);iCre(+) mice show reduced fertility. These studies show that deletion of MEK1/2 in Leydig cells results in Leydig cell hypoplasia, hypoandrogenemia, and reduced fertility.
authors.affiliation: Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Soichi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Ping
authors.initials: P
authors.lastname: Tai
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.forename: CheMyong
authors.initials: C
authors.lastname: Ko
authors.forename: Mario
authors.initials: M
authors.lastname: Ascoli
mesh_terms: D000818:Animals; D001835:Body Weight; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D005298:Fertility; D047109:Fetal Development; D007006:Hypogonadism / Q000235:genetics; D007985:Leydig Cells / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009929:Organ Size; D046468:Sexual Development; D013737:Testis / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013739:Testosterone / Q000378:metabolism
chemical_list: D013739:Testosterone; D000242:Cyclic AMP; D002786:Cholesterol Side-Chain Cleavage Enzyme; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C090864:Ddx4 protein, mouse; D053487:DEAD-box RNA Helicases