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 post-meiotic 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.

Essential Role of the p110β Subunit of Phosphoinositide 3-OH Kinase in Male Fertility

CIRAOLO, Elisa;MORELLO, Fulvio;LU, Xiaoyun;Giulio Mengozzi;ALTRUDA, Fiorella;SORBA, Giovanni;PANDOLFI DE RINALDIS, Pier Paolo;HIRSCH, Emilio
2010

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 post-meiotic 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.
21
5
704
711
http://www.molbiolcell.org/cgi/reprint/21/5/704
Elisa Ciraolo; Fulvio Morello; Robin M. Hobbs; Frieder Wolf; Romina Marone; Manuela Iezzi; Xiaoyun Lu; Giulio Mengozzi; Fiorella Altruda; Giovanni Sorba; Kaomei Guan; Pier Paolo Pandolfi; Matthias P. Wymann; Emilio Hirsch
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/72513
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