Defects in efferent duct multiciliogenesis underlie male infertility in GEMC1-, MCIDAS- or CCNO-deficient mice

GEMC1 and MCIDAS are geminin family proteins that transcriptionally activate E2F4/5-target genes during multiciliogenesis, including and Male mice that lacked , or were found to be infertile, but the origin of this defect has remained unclear. Here, we show that all three genes are necessary for the generation of functional multiciliated cells in the efferent ducts that are required for spermatozoa to enter the epididymis. In mice that are mutant for , or , we observed a similar spectrum of phenotypes, including thinning of the seminiferous tubule epithelia, dilation of the rete testes, sperm agglutinations in the efferent ducts and lack of spermatozoa in the epididymis (azoospermia). These data suggest that defective efferent duct development is the dominant cause of male infertility in these mouse models, and this likely extends to individuals with the ciliopathy reduced generation of multiple motile cilia with mutations in and .