Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Characterisation of a novel role for the dynamin mechanoenzymes in the regulation of human sperm acrosomal exocytosis (#97)

Wei Zhou 1 , Amanda L Anderson 1 , Adrian P Turner 2 , Geoffry N De Iuliis 1 , Adam McCluskey 1 , Eileen A McLaughlin 1 2 , Brett Nixon 1
  1. University of Newcastle, Callaghan, NSW, Australia
  2. School of Biological Sciences, University of Auckland, Auckland , New Zealand

The completion of an acrosome reaction is a prerequisite for successful fertilisation and accordingly, failure to complete this unique exocytotic event represents a common aetiology underpinning the defective sperm function of infertile males. In recent studies conducted in the mouse model, we have firmly implicated the dynamin family of mechanoenzymes as important regulators of acrosomal exocytosis. Here we extend these studies to provide the first evidence that the three canonical dynamin isoforms (DNM1, DNM2, and DNM3) are present in human spermatozoa. Further, the localisation of DNM1 and DNM2 to the peri-acrosomal domain ideally positions these isoforms to exert a regulatory role over acrosomal exocytosis. Consistent with such a role, we demonstrate that pharmacological inhibition of DNM1 and DNM2 is able to significantly suppress the rates of acrosomal exocytosis achieved following progesterone stimulus. In contrast, no such inhibition was observed when acrosomal exocytosis was induced via a calcium ionophore, which is capable of bypassing physiological control of this exocytotic reaction. The importance of such findings was further emphasised by the apparent reduction in DNM2 among poor quality spermatozoa that were refractory to the induction of a progesterone-stimulated acrosome reaction. In seeking to identify the regulatory influence of progesterone on DNM2 function, we were able to establish that the protein is a substrate for CDK1-dependent phosphorylation. The functional significance of DNM2 phosphorylation was illustrated by the fact that pharmacological inhibition of CDK1 elicited a concomitant suppression of both DNM2-Ser764 phosphorylation and the overall rates of progesterone induced acrosomal exocytosis. Overall, this study has identified a novel causative link between dynamin activity and the ability of human spermatozoa to complete a progesterone-induced acrosome reaction. Such findings encourage a more detailed analysis of the contribution of dynamin dysregulation as an underlying aetiology in infertile males whose spermatozoa are unable to penetrate the zona pellucida.