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.

Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors

“…These constitutive mutant mice mimic, to some extent, the effects of systemic administration of isoform selective PI3K inhibitors (22, 32, 33). Given that homozygous p110α D933A/D933A and p110β D931A/D931A KI mice die during embryonic development (21, 22), we crossed heterozygous p110α D933A/WT , p110β D931A/WT , and p110δ D910A/WT (WT is the wild-type allele; Fig. 3C-E) with RIP1-Tag2 mice (further referred to as RIP1-Tag2-p110α D933A/WT , RIP1-Tag2-p110β D931A/WT , and RIP1-Tag2-p110δ D910A/WT ).…”

“…3C-E) with RIP1-Tag2 mice (further referred to as RIP1-Tag2-p110α D933A/WT , RIP1-Tag2-p110β D931A/WT , and RIP1-Tag2-p110δ D910A/WT ). Of note, the heterozygous p110 kinase-dead mutants have been crucial in understanding the physiological roles of these isoforms as they show an intermediate phenotype in cultured cells and in mice compared to homozygous mutants, indicating a dose-dependent activity of these PI3K isoforms (22, 32, 33). …”

“…Heterozygous p110α D933A/WT (Ref (21)), p110β D931A/WT (Ref (22)), and p110δ D910A/WT (Ref (23)), RIP1-Tag2 (Ref(20)) were backcrossed onto the C57/BL6 background for >10 generations and WT littermates used as controls.…”

OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis

“…This finding provided further evidence to support the notion that there is an increased proportion of SCs in DKO mice. We next examined the expression of genes for selected differentiation markers (A-Myb, PABP, TP1 and protamine1)303132333435 in the testes of DKO mice. The expression of all these markers was undetectable in the testes of DKO mice at 5 months of age (Fig.…”

C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia

“…Genetic and pharmacological studies have moreover established that p110a is critical in transducing the metabolic actions of insulin (5, 6), however it is also coupled to a wide range of other receptor tyrosine kinases. p110δ is predominantly important in lymphocytes, and activating mutations cause autosomal dominant immunodeficiency (7), while the role of the ubiquitous p110β has been less precisely defined (8).…”