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PLoS Genet. 2015 Jul 1;11(7):e1005304. doi: 10.1371/journal.pgen.1005304. eCollection 2015 Jul.

Novel Role for p110β PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells.

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UCL Cancer Institute, University College London, London, United Kingdom; Centre de Recherche en Cancérologie de Toulouse UMR1037, INSERM, BP84225, Toulouse, France; Université Toulouse III-Paul Sabatier, Toulouse, France.
MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, UEB, SFR BIOSIT UMS 3480, Faculté de Médecine, Rennes, France.
UCL Cancer Institute, University College London, London, United Kingdom.
Physiologie de la Reproduction et des Comportements, UMR 7247 INRA-CNRS-Université de Tours, Nouzilly, France.
Astra Zeneca, Research and Development, Mölndal, Mölndal, Sweden.
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
UCL Cancer Institute, University College London, London, United Kingdom; Vascular Signalling Laboratory, Institut d´Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L´Hospitalet de Llobregat, Barcelona, Spain.
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
Astrazeneca Oncology iMED, Alderley Park, Macclesfield, Cheshire, United Kingdom.
MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom, and Department of Physiology, University of Turku, Turku, Finland.


The organismal roles of the ubiquitously expressed class I PI3K isoform p110β remain largely unknown. Using a new kinase-dead knockin mouse model that mimics constitutive pharmacological inactivation of p110β, we document that full inactivation of p110β leads to embryonic lethality in a substantial fraction of mice. Interestingly, the homozygous p110β kinase-dead mice that survive into adulthood (maximum ~26% on a mixed genetic background) have no apparent phenotypes, other than subfertility in females and complete infertility in males. Systemic inhibition of p110β results in a highly specific blockade in the maturation of spermatogonia to spermatocytes. p110β 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 p110β also plays a germ cell-extrinsic role in the Sertoli cells (SCs) that support the developing sperm, with p110β 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 p110β inactivation. In line with a crucial role for p110β in SCs, selective inactivation of p110β 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 p110β and AR have previously been reported to functionally interact.

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