A Y-encoded subunit of the translation initiation factor Eif2 is essential for mouse spermatogenesis

In mouse and man, deletions of specific regions of the Y chromosome have been linked to early failure of spermatogenesis and consequent sterility; the Y chromosomal gene(s) with this essential early role in spermatogenesis have not been identified. The partial deletion of the mouse Y short arm (the Sxr(b) deletion) that occurred when Tp(Y)1Ct(Sxr-b) (hereafter Sxr(b)) arose from Tp(Y)1CT(Sxr-b) (hereafter Sxr(a)) defines Spy, a Y chromosomal factor essential for normal spermatogonial proliferation(1-3). Molecular analysis has identified six genes that lie within the deletion: Ube1y1 (refs. 4,5), Smcy(6), Uty(7), Usp9y (also known as Dffry)(8), Eif2s3y (also known as Eif-2 gammaY)(9) and Dby(10); all have closely similar X-encoded homologs. of the Y-encoded genes, Ube1y1 and Dby have been considered strong candidates for mouse Spy function(4,5,10,11), whereas Smcy has been effectively ruled out as a candidate(12). There is no Ube1y1 homolog in man, and DBY, either alone or in conjunction with USP9Y, is the favored candidate for an early spermatogenic role(10,13-15). Here we show that introduction of Ube1y1 and Dby as transgenes. into Sxr(b)-deletion mice fails to overcome the spermatogenic block. However, the introduction of Eif2s3y restores normal spermatogonial proliferation and progression through meiotic prophase. Therefore, Eif2s3y, which encodes a subunit of the eukaryotic translation initiation factor Eif2, is Spy.