In a subset of infertile men, a spectrum of spermatogenic defects ranging f
rom a complete absence of germ cells (sertoli cell only) to oligozoospermia
is associated with microdeletions, of the DAZ (deleted in azoospermia) gen
e cluster on human distal Yq. DAZ encodes a testis-specific protein with RN
A-binding potential recently derived from a single-copy gene DAZL1 (DAZ-lik
e) on chromosome 3. Y chromosomal DAZ homologues are confined to humans and
higher primates. It remains unclear which function unique to higher primat
e spermatogenesis DAZ may serve, and the functional status of the gene rece
ntly has been questioned. To assess the extent of functional conservation w
e have tested the capacity of-a humanDAZ gene contained in a 225-kb yeast a
rtificial chromosome to complement the sterile phenotype of the Dad null mo
use (Dazl(-/-)), which is characterized by severe germ-cell depletion and m
eiotic failure. Although Dazl(-/-) mice remained infertile when the DAZ tra
nsgene was introduced, histological examination revealed a partial and vari
able rescue of the mutant phenotype, manifest as a pronounced increase in t
he germ cell population of the seminiferous tubules and survival to the pac
hytene stage of meiosis. As well as constituting definitive proof of the sp
ermatogenic role of the DAZ gene product, these findings confirm the high d
egree of functional conservation between the DAZ and DAZL1 genes, suggestin
g they may constitute a single target for contraceptive intervention and ra
ising the possibility of therapeutic up-regulation of the DAZL1 gene in inf
ertile men.