Importin a7 deficiency causes infertility in male mice by disrupting spermatogenesis

Spermatogenesis, a fundamental process in male reproduction, is driven by an ordered series of events, which rely on the trafficking of specific proteins between nucleus and cytoplasm. The importin a family of proteins mediates movement of specific cargo proteins when bound to importin ß. Importin a genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here we use a loss-of-function approach to specifically determine the role of importin a7 (Kpna6) in spermatogenesis and male fertility. We show that ablation of importin a7 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells culminating in oligozoospermia. Importin a7-deficient mice exhibit an impaired Sertoli cell function, including loss of Sertoli cells from the seminiferous epithelium and a compromised nuclear transport of the androgen receptor. Furthermore, our data demonstrate devastating defects in spermiogenesis that are accompanied by a disturbed histone-protamine-exchange in elongating spermatids, resulting in incomplete sperm maturation and a massive loss of sperms. Our work uncovers the essential role of importin a7 in spermatogenesis and hence in male fertility. Overall design: The transcriptomes of testes obtained from Importin a7-/- and a7?IBB/?IBB mice was compared with those from C57Bl6/N by RNAseq in triplicate