• PMID: 26132308
• Gene Name: PIK3CB
• Condition: Role in spermatogenesis
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Role in spermatogenesis

Novel Role for p110? PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells

Guillermet-Guibert J, Smith LB, Halet G, Whitehead MA, Pearce W, Rebourcet D, León K, Crépieux P, Nock G, Strömstedt M, Enerback M, Chelala C, Graupera M, Carroll J, Cosulich S, Saunders PT, Huhtaniemi I, Vanhaesebroeck B.

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. FAU - Guillermet-Guibert, Julie AU - Guillermet-Guibert J AD - 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. FAU - Smith, Lee B AU - Smith LB AD - MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom. FAU - Halet, Guillaume AU - Halet G AD - 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. FAU - Whitehead, Maria A AU - Whitehead MA AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Pearce, Wayne AU - Pearce W AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Rebourcet, Diane AU - Rebourcet D AD - MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom. FAU - León, Kelly AU - León K AD - Physiologie de la Reproduction et des Comportements, UMR 7247 INRA-CNRS-Université de Tours, Nouzilly, France. FAU - Crépieux, Pascale AU - Crépieux P AD - Physiologie de la Reproduction et des Comportements, UMR 7247 INRA-CNRS-Université de Tours, Nouzilly, France. FAU - Nock, Gemma AU - Nock G AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Strömstedt, Maria AU - Strömstedt M AD - Astra Zeneca, Research and Development, Mölndal, Mölndal, Sweden. FAU - Enerback, Malin AU - Enerback M AD - Astra Zeneca, Research and Development, Mölndal, Mölndal, Sweden. FAU - Chelala, Claude AU - Chelala C AD - Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom. FAU - Graupera, Mariona AU - Graupera M AD - 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. FAU - Carroll, John AU - Carroll J AD - Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia. FAU - Cosulich, Sabina AU - Cosulich S AD - Astrazeneca Oncology iMED, Alderley Park, Macclesfield, Cheshire, United Kingdom. FAU - Saunders, Philippa T K AU - Saunders PT AD - MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom. FAU - Huhtaniemi, Ilpo AU - Huhtaniemi I AD - Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom, and Department of Physiology, University of Turku, Turku, Finland.