Odf2 haploinsufficiency causes a new type of decapitated and decaudated spermatozoa, Odf2-DDS, in mice

Abstract

Outer dense fibre 2 (Odf2 or ODF2) is a cytoskeletal protein required for flagella (tail)-beating and stability to transport sperm cells from testes to the eggs. There are infertile males, including human patients, who have a high percentage of decapitated and decaudated spermatozoa (DDS), whose semen contains abnormal spermatozoa with tailless heads and headless tails due to head-neck separation. DDS is untreatable in reproductive medicine. We report for the first time a new type of Odf2-DDS in heterozygous mutant Odf2+/− mice. Odf2+/− males were infertile due to haploinsufficiency caused by heterozygous deletion of the Odf2 gene, encoding the Odf2 proteins. Odf2 haploinsufficiency induced sperm neck-midpiece separation, a new type of head-tail separation, leading to the generation of headneck sperm cells or headnecks composed of heads with necks and neckless tails composed of only the main parts of tails. The headnecks were immotile but alive and capable of producing offspring by intracytoplasmic headneck sperm injection (ICSI). The neckless tails were motile and could induce capacitation but had no significant forward motility. Further studies are necessary to show that ICSI in humans, using headneck sperm cells, is viable and could be an alternative for infertile patients suffering from Odf2-DDS.

The multi-scale architecture of mammalian sperm flagella and implications for ciliary motility

“…Instead, mouse sperm have two electron-dense structures flanking the SCs (asterisks in Fig. 3c,f) , an arrangement reminiscent of the distribution pattern of the centrosomal protein speriolin (Goto et al, 2010; Ito et al, 2019).…”

Genetic loss of importin α4 causes abnormal sperm morphology and impacts on male fertility in mouse

“…41 In addition, haploinsufficiency of ODF2 induced sperm neck-midpiece separation resulting in decapitated and decaudated spermatozoa in mice. 42 These data suggest the loss of importin α4 affects multiple proteins structurally important in maintaining sperm integrity, resulting in phenotypes such as multiple flagella with one sperm head. To understand this phenomenon, we will further investigate how importin α4 maintains sperm formation in terms of dynamic changes in the germ cells.…”

“…For example, SPAG4 is a spermatid‐specific LINC component involved in tightening the sperm head‐to‐tail anchorage, and interacts with the outer dense fiber protein, ODF1 41 . In addition, haploinsufficiency of ODF2 induced sperm neck‐midpiece separation resulting in decapitated and decaudated spermatozoa in mice 42 . These data suggest the loss of importin α4 affects multiple proteins structurally important in maintaining sperm integrity, resulting in phenotypes such as multiple flagella with one sperm head.…”

“…It would also be interesting to identify which cargo proteins are inappropriately localized to the cytoplasm by the loss of importin α4. Our proteomics analysis provides clues to determine the functional significance of importin α4 in nuclear‐cytoplasmic transport in adult testis by identifying several abnormally expressed proteins in KO testis, including ODF2, 42,47 SPAG4, 48 CHDH, 49 and PRSS37, 50 which play significant roles in determining structurally integral spermatozoa. Additionally, it has also been demonstrated that the importin β family members RANBP17 and importin 13 play important roles in the nuclear‐cytoplasmic transport event during spermatogenesis 51,52 .…”

Dlec1 is required for spermatogenesis and male fertility in mice

“…Electron microscopy. Electron microscopy was performed, as previously described 52 . Briefly, mouse testes were fixed by perfusion with 4% PFA, followed by immersion fixation in 2.5% glutaraldehyde overnight at 4 °C.…”