X-gene functions in spermatogonia, and their role in idiopathic and sex chromosome aneuploidy associated infertility.

The sex chromosomes underscore basic differences between males and females, and the X and Y chromosomes have specialized functions in the gonad and germ cells. Sex chromosome aneuploidies, i.e. Klinefelter (XXY), Turner (XO) and double-Y (XYY) syndromes), form the largest group of chromosomal abnormalities and are associated with infertility. While recent studies have defined the mechanisms for germ cell loss in XO and XYY mice, Klinefelter syndrome (KS) infertility remains poorly understood. KS males experience an early spermatogonial block and germ cell loss initiates in utero. The early loss of gonadal function has significant long-term consequences. Gametogenesis in males occurs throughout their lifespan and relies on germline (spermatogonial) stem cells (SSCs), differing with females. Recent work from our group has identified the concerted activity of gene networks in driving spermatogenesis, and unique regulation of X-linked genes during this process. We observe that a number of X-genes express specifically in SSCs. However, regulation of SSCs self-renewal vs. differentiation dynamics, and the functional importance of X-linked genes in this process, remain poorly understood. We aim to understand physiological gene regulatory networks functional in SSCs using a combination of single-cell methods, to explain how perturbation in X-gene dosage in SSCs may cause infertility.