title: Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility.
abstract: Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110beta develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility. The examination of testes from p110beta-defective tubules demonstrates a widespread loss in spermatogenic cells, due to defective proliferation and survival of pre- and postmeiotic cells. In particular, p110beta is crucially needed in c-Kit-mediated spermatogonial expansion, as c-Kit-positive cells are lost in the adult testis and activation of Akt by SCF is blocked by a p110beta inhibitor. These data establish that activation of the p110beta PI3K isoform by c-Kit is required during spermatogenesis, thus opening the way to new treatments for c-Kit positive testicular cancers.
authors.affiliation: Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.forename: Fulvio
authors.initials: F
authors.lastname: Morello
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Frieder
authors.initials: F
authors.lastname: Wolf
authors.forename: Romina
authors.initials: R
authors.lastname: Marone
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Giulio
authors.initials: G
authors.lastname: Mengozzi
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorba
authors.forename: Kaomei
authors.initials: K
authors.lastname: Guan
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D053713:Azoospermia; D002384:Catalysis; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D005298:Fertility; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009845:Oligospermia; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D020033:Protein Isoforms; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013091:Spermatogenesis; D013736:Testicular Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D020033:Protein Isoforms; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit