324. SLX4, A KEY REGULATOR OF MEIOSIS AND DNA REPAIR IN THE MALE GERMLINE
I. R. Bernstein A B , E. A. McLaughlin A B and M. K. O’Bryan B CA Environmental and Life Sciences, The University of Newcastle, Callaghan, 2308, Australia.
B ARC Centre of Excellence in Biotechnology and Development, Australia.
C Monash University, Department of Anatomy and Developmental Biology, Clayton, VIC, Australia.
Reproduction, Fertility and Development 22(9) 124-124 https://doi.org/10.1071/SRB10Abs324
Published: 6 September 2010
Abstract
Genome integrity relies on the ability of DNA repair proteins to open, cleave and recombine DNA. Slx4 (synthetic lethal of unknown function) or BTBd12 (BTBD12 domain-containing protein 12) the human homologue is a DNA repair protein which has multiple independent cellular roles. Importantly, it is a component in Holliday junction homologous recombination (HR) where it interacts with other proteins to repair double strand breaks (DSB). SLX4 forms a heterodimer complex with SLX1, an endonuclease, in response to DNA damage. This complex works by recruiting several associated proteins including XPF- ERCC1 a 3′ flap endonuclease, to DSB allowing proper single strand annealing repair of the DNA. An essential part of meiosis in the male and female germ cell formation is DNA recombination which is initiated by DSB. Meiotic error at this stage can cause aneuploidy and infertility. As SLX4 acts as a key regulator of recombination we proposed that loss of this protein would cause dysfunction in germ cell development. Breeding pairs of SLX4+/– heterozygous mice were obtained from EUCOMM and germline transmission of the null allele confirmed. Adult mice were normal and healthy but analysis of the male reproductive tract confirmed abnormally small testes (wt+/– vs testes). Further investigation demonstrated hypospermatogenesis with major loss of meiotic spermatocytes and post meiotic and spermatids. Epididymal sperm retrieval confirmed that the SLX4–/– male does produce poorly motile sperm with significant acrosomal abnormalities and associated failure of sperm-zona pellucida binding (2.5 ± 1.6 vs 13.6 ± 3.6 sperm bound) when compared to heterozygote or wild type littermates. Interestingly the female SLX4 null mouse also has small ovaries compared with het and wt littermates (wt vs null). Histomorphological analysis reveals a significant reduction in the ovarian follicle pool compared to wild type littermates with concomitant increased levels of apoptosis. Early breeding trials confirm significant loss of fertility in null males and females probably due to deficient sperm development and oocyte dysfunction. Our study now aims to further examine the role of SLX4 in germ cell development in the testes and ovary and its impact on infertility.
