Novel Role for p110[Beta] PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells e1005304

• Published in: PLoS genetics Vol. 11; no. 7
• Main Authors: Guillermet-Guibert, Julie, Smith, Lee B, Halet, Guillaume, Whitehead, Maria A, Pearce, Wayne, Rebourcet, Diane, León, Kelly, Crépieux, Pascale, Nock, Gemma, Strömstedt, Maria, Enerback, Malin, Chelala, Claude, Graupera, Mariona, Carroll, John, Cosulich, Sabina, Saunders, Philippa TK, Huhtaniemi, Ilpo, Vanhaesebroeck, Bart
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01.07.2015
• Subjects: Colleges & universities; Enzymes; Experiments; Gene expression; Infertility; Kinases; Medical research; Metabolism; Proteins; Rodents; Sperm; Spermatogenesis; University colleges
• ISSN: 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005304

The organismal roles of the ubiquitously expressed class I PI3K isoform p110[Beta] remain largely unknown. Using a new kinase-dead knockin 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 ~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.