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Abstract
ABSTRACTSpermatogenesis is driven by an ordered series of events, which rely on trafficking of specific proteins between nucleus and cytoplasm. The karyopherin α family of proteins mediates movement of specific cargo proteins when bound to karyopherin β. Karyopherin α 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 determine specifically the role of Kpna6 in spermatogenesis and male fertility. We show that ablation of Kpna6 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells. Kpna6-deficient mice exhibit impaired Sertoli cell function, including loss of Sertoli cells and a compromised nuclear localization of the androgen receptor. Furthermore, our data demonstrate devastating defects on spermiogenesis, including incomplete sperm maturation and a massive reduction in sperm number, accompanied by disturbed histone-protamine exchange, differential localization of the transcriptional regulator BRWD1 and altered expression of RFX2 target genes. Our work uncovers an essential role of Kpna6 in spermatogenesis and, hence, in male fertility.
Highlights
The best-characterized mechanism of nuclear import involves karyopherin α and karyopherin β
Only a truncated non-functional Kpna6 was found in the Kpna6ΔIBB/ΔIBB testes (Fig. 1B), which resulted in male infertility, suggesting that Kpna6 is essential for male fertility
These findings are in accordance with the phenotype of fruit flies lacking karyopherin α1, which is one karyopherin α paralogs in Drosophila melanogaster with the highest similarity to mouse Kpna6
Summary
The best-characterized mechanism of nuclear import involves karyopherin α and karyopherin β ( known as importin α and importin β). Karyopherin α proteins are composed of three main structural domains: an N-terminal region, which is the karyopherin (importin) β binding (IBB) domain; a central domain containing Armadillo motifs; and a weakly conserved C-terminal region. The central domain of karyopherin α binds nuclear localization signals that are present in the target cargo proteins. Karyopherin α binds to karyopherin β via its IBB domain forming a. Handling Editor: Patrick Tam Received November 2020; Accepted August 2021 trimeric transport complex, which is translocated into the nucleus via karyopherin β interactions with nucleoporins lining the nuclear pore complex (Macara, 2001; Miyamoto et al, 2012). Three karyopherin α subtypes have been identified in Caenorhabditis elegans and Drosophila melanogaster, whereas up to seven karyopherin α isoforms have been found in mammals (Köhler et al, 1997; Tejomurtula et al, 2009; Tsuji et al, 1997)
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