title: Novel Role for p110β PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Halet
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Whitehead
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Diane
authors.initials: D
authors.lastname: Rebourcet
authors.affiliation: Physiologie de la Reproduction et des Comportements, UMR 7247 INRA-CNRS-Université de Tours, Nouzilly, France.
authors.forename: Kelly
authors.initials: K
authors.lastname: León
authors.affiliation: Physiologie de la Reproduction et des Comportements, UMR 7247 INRA-CNRS-Université de Tours, Nouzilly, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Crépieux
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Gemma
authors.initials: G
authors.lastname: Nock
authors.affiliation: Astra Zeneca, Research and Development, Mölndal, Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Strömstedt
authors.affiliation: Astra Zeneca, Research and Development, Mölndal, Mölndal, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Enerback
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: 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.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Carroll
authors.affiliation: Astrazeneca Oncology iMED, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom, and Department of Physiology, University of Turku, Turku, Finland.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D007247:Infertility, Female / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009028:Morula / Q000166:cytology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D011944:Receptors, Androgen; C498048:Rhox5 protein, mouse; D014157:Transcription Factors; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases