Presentation Authors: Carolina Jorgez, Jason Scovell*, Abhishek Seth, Nathan Wilken, Juan Bournat, Houston, TX, Dolores Lamb, New York, NY
Introduction: Infertility affects 15% of couples trying to conceive. The etiology for most cases of male infertility is unknown. However, a well-recognized contributing cause of male infertility is cryptorchidism, the most common birth defect in men. Gene-dosage changes resulting from microdeletions and microduplications encompassing E2F1 are present in a subset of infertile men, including some that were cryptorchid. It was hypothesized that gene-dosage changes in E2f1 can cause cryptorchidism.
Methods: Detailed phenotypic analyses of E2f1 null mice were conducted to assess testicular development, location and function.
Results: E2f1-null mice had inguinal cryptorchidism with severe structural defects of the gubernaculum and progressive loss of testicular germ cells that culminated in infertility. Testicular failure was associated with significantly decreased testicular weight and impaired sperm production. Inactivation of E2f1 resulted in the loss of germ cell polarity and abnormal tight junction assembly, which in turn contributed to germ cell loss. Abnormalities in cell cycle gene expression were identified. Germ cell depletion in the adult mice did not occur by apoptosis. Testicular Wnt4 gene and protein expression significantly increased as E2f1-null mice matured and aged. To validate that the increase in Wnt4 expression played a role in the fertility defects, E2f1-null mice were crossed to Wnt4-flox and Stra8-Cre mice to delete Wnt4 in the germ cells. Mice lacking E2f1 and Wnt4 in germ cell had normal fertility. Thus, in the absence of E2f1, increased WNT4 expression negatively impacted mouse spermatogenesis, as shown by the normal male fertility of the double-null mouse model.
Conclusions: E2F1 plays an important role in testicular descent and function. In the absence of E2f1, increased Wnt4 expression correlated with germ cell loss, suggesting a novel role of Wnt4 in spermatogonial germ cell survival, and E2f1 as a repressor of Wnt4 in the testis. These results suggest that E2f1 governs developmental events in the testis causing inappropriate upregulation of Wnt4 that gave rise to spermatogenic failure and infertility.
Source of Funding: This study was supported in part by the NIH Multidisciplinary K12 Urologic Research (KURe) Career Development Program K12DK0083014 to DJL (CJ and AS were K12 scholars). DJL is also supported in part by the Frederick J. and Theresa Dow Wallace Fund of the