Null mutation of the transcription factor inhibitor of DNA binding 3 (ID3) in male mice adversely impacts on fertility and reproductive outcome.

Inhibitor of DNA binding 3 (ID3) protein binds to and inhibits the function of basic helix-loop-helix transcription factors. The expression of ID3 protein in postproliferative Sertoli cells in the testis, as well as its unique, highly region-specific expression profile along the adult epididymis, implies novel functional roles for this regulator of transcription. The purpose of this study was to determine the effect of Id3 deficiency on male fertility and progeny outcome. We observed that fertility status of Id3(-/-) males is adversely affected. Males having this null mutation did not sire any litters when crossed with wild-type C57Bl/6 females; although pregnancies were induced in these females, these never resulted in the birth of live pups. Additionally, abnormal reproductive outcomes and developmental phenotypes were observed in gestational day 18 fetuses resulting from crosses with an Id3-deficient sire and wild-type CD-1 females; these were characterized by an elevated rate of fetal death, reduced body weights of live fetuses, a higher rate of external malformations, and aberrant skeletal development. Importantly, we observed that mutation of this gene differentially affects the phenotype of resulting offspring, depending on the genotype of the parent, not necessarily the genotype of the fetus itself. These results provide novel insight into the role of Id3, suggesting that Id3 might coordinate gene expression programs in the male reproductive system associated with the generation of healthy offspring.