Ikbkap/Elp1 Deficiency Causes Male Infertility by Disrupting Meiotic Progression

Fu-Jung Lin,Li Shen,Yi Zhang,Pål Ø Falnes,Chuan-Wei Jang,John C Schimenti

doi:10.1371/journal.pgen.1003516

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.

Highlights

Meiosis is a fundamental and highly regulated process that takes place during gamete generation
The process of meiosis is responsible for gamete formation and ensures that offspring will inherit a complete set of chromosomes from each parent
Many genes that are essential in regulating meiosis have been implicated in DNA repair

Summary

Introduction

Meiosis is a fundamental and highly regulated process that takes place during gamete generation. Faithful execution of this process is essential for maintaining genome integrity. Synapsis is mediated by a protein complex namely the synaptonemal complex (SC), and is accompanied by chromosome recombination [2]. Formation of the fully synapsed autosomal SCs as well as the partially synapsed sex chromosome are essential for DNA repair, recombination and subsequent desynapsis [4]. DNA damage response (DDR) is initiated upon the recognition of the DNA lesion made by SPO11, which is a type II-like topoisomerase that induces double-stranded breaks (DSBs) [5]. At the DSB sites, the DNA repair machinery generates DNA recombination between homologous chromosomes to ensure proper disjunction at metaphase I. The genetic studies in yeast and mouse helped identify many factors important for meiosis [6,7,8], such as: the master regulators meiosis-inducing protein 1 (Ime1) in yeast, and A-MYB (MYBL1)

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