Insulin Receptor Substrate 2 is Required for Testicular Development

Abstract

Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) 1 signaling. In mice, deletion of Irs2 causes diabetes and females are infertile. However, the role of IRS2 in male reproduction is unknown. Therefore, the objectives of these studies were to determine if Irs2-deficiency alters testicular development and function. Irs2-deficient adult and neonatal male mice exhibited reduced testicular size and weight. There was a reduction in the number of Sertoli cells, spermatogonia, spermatocytes, and spermatozoa, however there were no differences in the number of Leydig cells or the concentration of testosterone in serum. Testicular morphology appeared unaffected, and there were normal cellular associations without obvious abnormalities in the seminiferous epithelium. Gene and protein expression of IRS1, 3, and 4 were unchanged in Irs2-deficient mice indicating that the other IRS proteins did not overcompensate for the loss of Irs2. Gene expression of growth hormone receptor and protein expression of SOX9 were significantly reduced in Irs2-deficient mice. There was increased phosphorylation of AKT, GSK3β, and ERK in the testes of Irs2-/- mice but no differences in protein expression of cell cycle regulatory proteins cyclin D or p27. In summary, the results from these studies demonstrate that IRS2 plays a critical role in the regulation of testis size, and that IRS2 may modulate testis size by reducing or delaying Sertoli cell proliferation during embryonic and early postnatal development. These results provide an important platform for further understanding the effects of IRS2 signaling and diabetes on male reproductive function

Date of Award	26 Sept 2012
Original language	English
Supervisor	Deborah J Burks (Director) & M. Teresa Paramio Nieto (Tutor)