Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility.
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.
Ciraolo
Elisa
E
Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
Morello
Fulvio
F
Hobbs
Robin M
RM
Wolf
Frieder
F
Marone
Romina
R
Iezzi
Manuela
M
Lu
Xiaoyun
X
Mengozzi
Giulio
G
Altruda
Fiorella
F
Sorba
Giovanni
G
Guan
Kaomei
K
Pandolfi
Pier Paolo
PP
Wymann
Matthias P
MP
Hirsch
Emilio
E
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
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