Loss of the Nuclear Receptor Corepressor SLIRP Compromises Male Fertility

Shane M Colley,D Jo Merriner,Richelle Searles,Ben Genevieve,Victoria Russell,Moira K O'Bryan,Stephanie Smith,Renee C Firman,Larissa Wintle,Leigh W Simmons,Bronwyn G A Stuckey,Michael R Phillips,David M De Kretser,Kathleen Deboer,Peter J Leedman,Jacqueline M Bentel

doi:10.1371/journal.pone.0070700

Abstract

Nuclear receptors (NRs) and their coregulators play fundamental roles in initiating and directing gene expression influencing mammalian reproduction, development and metabolism. SRA stem Loop Interacting RNA-binding Protein (SLIRP) is a Steroid receptor RNA Activator (SRA) RNA-binding protein that is a potent repressor of NR activity. SLIRP is present in complexes associated with NR target genes in the nucleus; however, it is also abundant in mitochondria where it affects mitochondrial mRNA transcription and energy turnover. In further characterisation studies, we observed SLIRP protein in the testis where its localization pattern changes from mitochondrial in diploid cells to peri-acrosomal and the tail in mature sperm. To investigate the in vivo effects of SLIRP, we generated a SLIRP knockout (KO) mouse. This animal is viable, but sub-fertile. Specifically, when homozygous KO males are crossed with wild type (WT) females the resultant average litter size is reduced by approximately one third compared with those produced by WT males and females. Further, SLIRP KO mice produced significantly fewer progressively motile sperm than WT animals. Electron microscopy identified disruption of the mid-piece/annulus junction in homozygous KO sperm and altered mitochondrial morphology. In sum, our data implicates SLIRP in regulating male fertility, wherein its loss results in asthenozoospermia associated with compromised sperm structure and mitochondrial morphology.

Highlights

Infertility affects approximately 1 in 8 couples globally, with the cause being attributable to a male factor in approximately half of all cases [1]
Data presented demonstrate that stem Loop Interacting RNA-binding Protein (SLIRP) is produced in murine testes and co-localizes to mitochondria in spermatogonia and early spermatocytes before shifting to peri-acrosomal in spermatids and to the acrosomal region and tail of mature sperm
SLIRP deletion is associated with male sub-fertility characterized by the production of sperm with reduced progressive motility, abnormalities in mitochondrial structure and the disjunction of the mitochondrial sheath and annulus

Summary

Introduction

Infertility affects approximately 1 in 8 couples globally, with the cause being attributable to a male factor in approximately half of all cases [1]. Determining the basis of infertility and providing effective and early screening for identified causes may lead to more effective clinical intervention. Multiple factors determine fertility and in particular spermatogenesis [2,3,4]. Mutations in genes critical to spermatogenesis and function have been found to cause defects to functional components of sperm including mitochondria [7,8], the acrosome [9], annulus [10] and flagellum [11]

Methods

Results

Conclusion