Hogarth – Vitamin A regulation of male reproduction
Infertility affects about 1 out of every 6 couples in Australia and in about 40% of these cases, the cause is attributed to the male partner. For the majority of these men, the reason for their infertility remains undiagnosed and is not treatable. Alternatively, there is also a growing demand and need for the development of novel contraceptive options for men. Vitamin A is known to be a master regulator of development and maturation of sperm. Our research examines how the active metabolite of vitamin A, retinoic acid, controls gene expression within different regions of the male reproductive tract and whether the enzymes responsible for the synthesis and degradation of retinoic acid are viable therapeutic targets for the treatment of male infertility or the development of novel male contraceptives.
Research areas
A mature sperm cell is the final product of a complex process of cell differentiation that begins with a germ line stem cell. It is well established that the active metabolite of vitamin A, retinoic acid (RA), plays an essential role in the transformation of germline stem cells into differentiated spermatogonia, the first cell type known to be committed to becoming a sperm. RA is a potent regulator of gene expression and one of its key target genes within spermatogonia is stimulated by retinoic acid gene 8 (STRA8). In the absence of STRA8, male germ cells are unable to progress through meiosis, the process require to generate haploid sperm. While we know that STRA8 is essential for the formation of sperm, its exact function remains unknown. Localization studies have shown that STRA8 protein is mostly present within the nucleus of spermatogonia but it is unclear what role STRA8 plays within this organelle. We are using super-resolution imaging technology to investigate where STRA8 localizes within the nucleus of spermatogonia and assess chromatin dynamics and epigenetic changes as male germ cells differentiate.
A sperm can only fertilize an egg once it’s passed through the epididymis, a long and highly coiled tube that stores sperm and transports them from the testis to the vas deferens. As sperm transit the epididymis, they acquire motility and the ability to fertilize an egg. The epididymis can be divided into three different regions, the caput (head), corpus (body) and cauda (tail). The main distinction between these three regions are different microenvironments created by variations in fluid along the tubule. It is these changes to the highly specialized luminal microenvironment that facilitates the maturation of sperm as they pass through the epididymis. The active metabolite of vitamin A, retinoic acid (RA), is a potent regulator of gene expression throughout the male reproductive tract and the epididymis produces very high concentrations of a specialized RA binding protein, ERABP, not found in any other organ. However, the function of RA activity within the epididymis and whether ERABP is essential to the maturation of sperm have yet to be investigated. Our lab is interested in determining whether RA exists in a gradient along the length of the epididymis, what role ERABP protein plays within this organ and what the direct effects of RA signaling are on epididymal function.
