Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

When splicing goes wrong: a mechanism for spermatid differentiation and lung tumourigenesis (#85)

Duangporn Jamsai 1 , Brett Clark 1 , Anne O'Connor 1 , Eileen McLaughlin 2 , Moira O'Bryan 1
  1. Monash University, Melbourne, VIC, Australia
  2. The University of Newcastle, Callaghan, NSW, Australia

The production of functional spermatozoa requires the coordinated activation of thousands of genes. It is likely that this complexity contributes to the large number of idiopathic infertility cases seen in humans. In an effort to improve the field’s understanding of male fertility, we used a genome-wide N-Ethyl-N-Nitrosourea (ENU) mutagenesis screen to produce several sterile mouse lines. Using these mice we have identified novel genes with essential roles in male fertility and other developmental processes. One such example of these genes is Rbm5 (RNA binding motif 5).

RBM5 is one of the genes frequently deleted in lung cancer patients and as such it has been proposed as a putative tumour suppressor. The physiological role of RBM5, however, has not been defined. In this study, we demonstrated an essential role for RBM5 in male fertility. Mice carrying an ENU-induced missense mutation (R263P) in the second RNA recognition motif of RBM5 exhibited spermatid differentiation arrest, germ cell sloughing and apoptosis, which ultimately led to male sterility. We showed that RBM5 is a splicing factor in the testis. The R263P mutation resulted in aberrant splicing of several RBM5 target pre-mRNAs, which in turn affected expression of genes that regulated germ cell adhesion, spermatid head shaping, and acrosome and tail formation. In addition to fertility defects in young mice, compromised RBM5 function resulted in an increased incidence of lung cancer in aged mice. These data strongly suggest that RBM5 is indeed a lung tumour suppressor. In the lung, RBM5 regulated the splicing of pre-mRNAs that played a role in cell proliferation, differentiation and apoptosis.

In summary, our findings demonstrate that RBM5 is critical splicing factor that regulates the splicing of specific subsets of pre-mRNAs in male germ cells and the lung. RBM5-medicated splicing regulation is pivotal for male fertility and lung tumour suppression.