Ikbkap/Elp1 Deficiency Causes Male Infertility by Disrupting Meiotic Progression

Abstract

Mouse Ikbkap gene encodes IKAP—one of the core subunits of Elongator—and is thought to be involved in transcription. However, the biological function of IKAP, particularly within the context of an animal model, remains poorly characterized. We used a loss-of-function approach in mice to demonstrate that Ikbkap is essential for meiosis during spermatogenesis. Absence of Ikbkap results in defects in synapsis and meiotic recombination, both of which result in increased apoptosis and complete arrest of gametogenesis. In Ikbkap-mutant testes, a few meiotic genes are down-regulated, suggesting IKAP's role in transcriptional regulation. In addition, Ikbkap-mutant testes exhibit defects in wobble uridine tRNA modification, supporting a conserved tRNA modification function from yeast to mammals. Thus, our study not only reveals a novel function of IKAP in meiosis, but also suggests that IKAP contributes to this process partly by exerting its effect on transcription and tRNA modification.

Author Summary

The process of meiosis is responsible for gamete formation and ensures that offspring will inherit a complete set of chromosomes from each parent. Errors arising during this process generally result in spontaneous abortions, birth defects, or infertility. Many genes that are essential in regulating meiosis have also been implicated in DNA repair. Importantly, defects in DNA repair are common causes of cancers. Therefore, identification of genes important for normal meiosis contributes not only to the field of reproduction but also to the field of cancer biology. We studied the effects of deleting mouse Ikbkap, a gene that encodes one of the subunit of the Elongator complex initially described as an RNA polymerase II–associated transcription elongation factor. We demonstrate that Ikbkap mutant mice exhibit infertility and defects in meiotic progression. Specifically, homologous and sex chromosomes fail to synapse (become associated), DNA double-strand breaks are inefficiently repaired, and DNA crossovers are significantly decreased in Ikbkap males. We also demonstrate that the requirement for Elongator in tRNA modification, which has been shown in lower eukaryotes, is conserved in mammals. Our findings suggest novel roles for Ikbkap in meiosis progression and tRNA modification, which have not been reported previously.