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Título:	Novel Role for p110β PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells
Autor/a:	Guillermet-Guibert, Julie; Smith, Lee B.; Halet, Guillaume; Whitehead, Maria A.; Pearce, Wayne; Rebourcet, Diane; León, Kelly; Crepieux, Pascale; Nock, Gemma; Strömstedt, Maria; Enerback, Malin; Chelala, Claude; Graupera i Garcia-Milà, Mariona; Carroll, John; Cosulich, Sabina; Saunders, Philippa T. K.; Huhtaniemi, Ilpo; Vanhaesebroeck, Bart
Abstract:	The organismal roles of the ubiquitously expressed class I PI3Kisoform p110 beta remain largely unknown. Using a new kinase- deadknockin mouse model that mimics constitutive pharmacological inactivation of p110 beta, we document that full inactivation of p110 beta leads to embryonic lethality in a substantial fraction of mice. Interestingly, the homozygous p110 beta kinase- dead mice that survive into adulthood (maximum similar to 26% on a mixed genetic background) have no apparent phenotypes, other than subfertility in females and complete infertility in males. Systemic inhibition of p110 beta results in a highly specific blockade in the maturation of spermatogonia to spermatocytes. p110 beta was previously suggested to signal downstream of the c- kit tyrosine kinase receptor in germ cells to regulate their proliferation and survival. We now report that p110 beta also plays a germ cell- extrinsic role in the Sertoli cells (SCs) that support the developing sperm, with p110 beta inactivation dampening expression of the SC- specific Androgen Receptor (AR) target gene Rhox5, a homeobox gene critical for spermatogenesis. All extragonadal androgen- dependent functions remain unaffected by global p110 beta inactivation. In line with a crucial role for p110 beta in SCs, selective inactivation of p110 beta in these cells results in male infertility. Our study is the first documentation of the involvement of a signalling enzyme, PI3K, in the regulation of AR activity during spermatogenesis. This developmental pathway may become active in prostate cancer where p110 beta and AR have previously been reported to functionally interact.
Materia(s):	-Expressió gènica -Fecunditat -Gene expression -Fertility
Derechos:	cc by (c) Guillermet-Guibert et al., 2015 http://creativecommons.org/licenses/by/3.0/es/
Tipo de documento:	Artículo Artículo - Versión publicada
Editor:	Public Library of Science (PLoS)
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