Novel role for p110 beta PI 3-Kinase in male fertility through regulation of androgen receptor activity in sertoli cells

Julie Guillermet-Guibert, Lee B Smith, Guillaume Halet, Maria A Whitehead, Wayne Pearce, Diane Rebourcet, Kelly Leon, Pascale Crepieux, Gemma Nock, Maria Stromstedt, Malin Enerback, Claude Chelala, Mariona Graupera, John Graham Carroll, Sabina Cosulich, Philippa T K Saunders, Ilpo Huhtaniemi, Bart M Vanhaesebroeck

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Abstract

The organismal roles of the ubiquitously expressed class I PI3K isoform p110beta remain largely unknown. Using a new kinase-dead knockin mouse model that mimics constitutive pharmacological inactivation of p110beta, we document that full inactivation of p110beta leads to embryonic lethality in a substantial fraction of mice. Interestingly, the homozygous p110beta 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 p110beta results in a highly specific blockade in the maturation of spermatogonia to spermatocytes. p110beta 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 p110beta also plays a germ cell-extrinsic role in the Sertoli cells (SCs) that support the developing sperm, with p110beta 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 p110beta inactivation. In line with a crucial role for p110beta in SCs, selective inactivation of p110beta 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 p110beta and AR have previously been reported to functionally interact.
Original languageEnglish
Article numbere1005304
Number of pages25
JournalPLoS Genetics
Volume11
Issue number7
DOIs
Publication statusPublished - 2015

Cite this

Guillermet-Guibert, J., Smith, L. B., Halet, G., Whitehead, M. A., Pearce, W., Rebourcet, D., Leon, K., Crepieux, P., Nock, G., Stromstedt, M., Enerback, M., Chelala, C., Graupera, M., Carroll, J. G., Cosulich, S., Saunders, P. T. K., Huhtaniemi, I., & Vanhaesebroeck, B. M. (2015). Novel role for p110 beta PI 3-Kinase in male fertility through regulation of androgen receptor activity in sertoli cells. PLoS Genetics, 11(7), [e1005304]. https://doi.org/10.1371/journal.pgen.1005304