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Deletions of the  AZFa  region ( AZoospermia Factor-a ) region of the human Y chromosome cause irreversible spermatogenic failure that presents clinically in men as Sertoli-cell only (SCO) pathology of the testis. Deletions of the  AZFa  region typically encompass two genes:  DDX3Y  and  USP9Y . However, human genetic evidence indicates that SCO is most tightly linked to deletion of  DDX3Y  and that deletions/mutations of  USP9Y  can be transmitted from one generation to the next. Here, we generated stable iPSC lines with  AZFa  deletions, tested complementation via introduction of  DDX3Y,  and assessed ability to form germ cells  in vivo  in a xenotransplantation model. We observed a quantifiable improvement in formation of germ cell like cells (GCLCs) from complemented donor iPSCs. Moreover, expression of UTF1, a prospermatogonial protein, was restored in cells complemented by introduction of  DDX3Y  on the  AZFa  background. Whole-genome RNA sequencing of purified GCLCs revealed an enrichment of genes involved in translational suppression and transcriptional control in  DDX3Y -rescued GCLCs over mutant GCLCs, which maintained a molecular phenotype more similar to undifferentiated iPSCs. This study demonstrates the ability to probe fundamental genetics of human germ cell formation by complementation and indicates that  DDX3Y  functions in the earliest stages of human germ cell development.

DDX3Y gene rescue of a Y chromosome AZFa deletion restores germ cell formation and transcriptional programs