Odf4, the outer dense fiber 4, is an integral protein that localizes to outer dense fibers (ODFs). Its function is mainly related to sperm-related biological processes. It is associated with adenylate kinases AK1 and AK2, and the Odf4-AK1-AK2 complex is crucial for normal sperm flagellar shape and movement, which are essential for fertility [1]. Also, as a cancer-testis antigen, it has potential biomarker significance in multiple cancers [2,3,5,6,7].

In Odf4-deletion (Odf4 -/-) mice, sperm flagella lose ODF4 and reduce AK1 and AK2 levels. The flagellum becomes bent (hairpin-shaped) with a large cytoplasmic droplet in the mid-piece. The mid-piece loses motility while the principal piece remains motile. These spermatozoa progress backward and fail to ascend in the uterus, leading to male infertility. However, in vitro fertilization experiments showed that Odf4 -/- spermatozoa can fertilize oocytes after undergoing capacitation in vitro, during which the large cytoplasmic droplets are removed and the flagella become straight [1,4].

In summary, Odf4 is essential for male fertility through its contribution to normal sperm flagellar shape and movement. Gene-knockout mouse models like Odf4 -/- mice have revealed its key role in male infertility. Additionally, its potential as a biomarker in cancers such as transitional cell carcinoma, breast cancer, chronic myeloid leukemia, and head and neck squamous cell carcinoma has been explored, providing new insights into disease diagnosis and treatment [1,2,3,4,5,6,7].

References:

1. Ito, Chizuru, Makino, Tsukasa, Mutoh, Tohru, Kikkawa, Masahide, Toshimori, Kiyotaka. 2023. The association of ODF4 with AK1 and AK2 in mice is essential for fertility through its contribution to flagellar shape. In Scientific reports, 13, 2969. doi:10.1038/s41598-023-28177-z. https://pubmed.ncbi.nlm.nih.gov/36804949/

2. Afsharpad, Mandana, Nowroozi, Mohammad Reza, Ayati, Mohsen, Zendehdel, Kazem, Modarressi, Mohammad Hossein. 2017. ODF4, MAGEA3, and MAGEB4: Potential Biomarkers in Patients with Transitional Cell Carcinoma. In Iranian biomedical journal, 22, 160-70. doi:. https://pubmed.ncbi.nlm.nih.gov/28865418/

3. Kazemi-Oula, Golnesa, Ghafouri-Fard, Soudeh, Mobasheri, Maryam Beigom, Geranpayeh, Lobat, Modarressi, Mohammad Hossein. 2015. Upregulation of RHOXF2 and ODF4 Expression in Breast Cancer Tissues. In Cell journal, 17, 471-7. doi:. https://pubmed.ncbi.nlm.nih.gov/26464818/

4. Ito, Chizuru, Mutoh, Tohru, Toshimori, Kiyotaka. 2024. Spermatozoa from male mice with infertility due to Odf4 deficiency can fertilize oocytes by in vitro fertilization. In Reproductive medicine and biology, 23, e12605. doi:10.1002/rmb2.12605. https://pubmed.ncbi.nlm.nih.gov/39314832/

5. Afsharpad, Mandana, Nowroozi, Mohammad Reza, Mobasheri, Maryam Beigom, Zendehdel, Kazem, Modarressi, Mohammad Hossein. 2017. Cancer-Testis Antigens as New Candidate Diagnostic Biomarkers for Transitional Cell Carcinoma of Bladder. In Pathology oncology research : POR, 25, 191-199. doi:10.1007/s12253-017-0313-4. https://pubmed.ncbi.nlm.nih.gov/29058301/

6. Ghafouri-Fard, Soudeh, Modarressi, Mohammad Hossein, Yazarloo, Fatemeh. . Expression of testis-specific genes, TEX101 and ODF4, in chronic myeloid leukemia and evaluation of TEX101 immunogenicity. In Annals of Saudi medicine, 32, 256-61. doi:10.5144/0256-4947.2012.256. https://pubmed.ncbi.nlm.nih.gov/22588436/

7. Liu, Shixian, Liu, Weiwei, Ding, Zhao, Liu, Yehai, Wu, Jing. 2022. Identification and validation of a novel tumor driver gene signature for diagnosis and prognosis of head and neck squamous cell carcinoma. In Frontiers in molecular biosciences, 9, 912620. doi:10.3389/fmolb.2022.912620. https://pubmed.ncbi.nlm.nih.gov/36339718/