First person – Stephen Wellard

Stephen Wellard

How would you explain the main findings of your paper in lay terms?

Mutations in Aurora kinase C cause male infertility, but a clear understanding of the meiotic roles of the three mammalian Aurora kinases has been lacking. To better understand how these kinases regulate chromosome segregation during spermatogenesis, we used a combination of chemical inhibition and genetic deletion approaches in mouse and human spermatocytes. We show that in both mice and humans, Aurora B and C activity is required to allow homologous chromosomes to desynapse, a necessary step prior to the first meiotic division. Interestingly, Aurora B and C kinases are functionally compensatory during spermatogenesis in mice; we found that deletion of Aurora B or Aurora C did not lead to meiotic defects or reduced fertility. The deletion of both Aurora B and C in mouse spermatocytes, however, led to increased levels of chromosome missegregation due to ineffective chromosome desynapsis and the misalignment of homologous chromosomes during the first meiotic division. These results emphasize the importance of maintaining Aurora B and C activity during spermatogenesis and offer insight into how Aurora C mutations could lead to infertility in humans.

Were there any specific challenges associated with this project? If so, how did you overcome them?

Because mutations in Aurora C cause infertility in men, we wanted to bridge our findings in mouse spermatocytes more closely to human biology. To do this, we obtained organ donor-derived human testes and isolated human primary spermatocytes. Adapting our protocols for the isolation and short-term culture of mouse spermatocytes to human spermatocytes was challenging, but allowed us to show that the function of Aurora B and C kinases in regulation of desynapsis is conserved in humans.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

Much of the early assessment of the Aurora B/C double-knockout mice focused on how these kinases regulate the disassembly of the synaptonemal complex, a proteinaceous scaffold that holds homologous chromosomes together during meiotic prophase. As such, these analyses were conducted using chromatin spread preparations with prophase-enriched populations of mouse spermatocytes. The first time I used a whole-cell staining approach to assess spermatocytes undergoing the first and second meiotic cell divisions, I was shocked by the levels of chromosome missegregation and cell death occurring in mouse spermatocytes lacking both Aurora B and C kinases. This experiment highlighted the consequences of the phenotype I had been assessing previously and underscored the importance of utilizing diverse experimental approaches to answer scientific questions.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

This study would not have been possible without the help and guidance we obtained from our collaborator Dr Karen Schindler. Her expertise on the roles of the Aurora kinases during mammalian oogenesis allowed us to identify the sexually dimorphic ways in which these kinases ensure chromosome segregation occurs without error during meiosis.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

Prior to entering graduate school, I gained additional research experience by working at the Naval Medical Research Center in Bethesda, Maryland. The group I worked with is developing a vaccine against Campylobacter jejuni, a bacterial pathogen that is a major cause of diarrheal disease worldwide. Their efforts to develop this vaccine are driven by a desire to protect the health of American service members and limit the burden of Campylobacter in developing countries, which results in high levels of childhood mortality. This experience shaped how I view the importance of basic scientific research, and how it can ultimately lead to significant public health advances.

What's next for you?

I am in the process of finding a postdoctoral position to continue my scientific training, and hope to stay in academia in the future.