• PMID: 30653527
• Gene Name: DCUN1D1
• Condition: Spermatogenesis defects
• Association: Associated
• Sex: Male
• Infertility type: Male infertility

Mouse DCUN1D1 (SCCRO) is required for spermatogenetic individualization

Huang G, Kaufman AJ, Ryan RJH, Romin Y, Huryn L, Bains S, Manova-Todorova K, Morris PL, Hunnicutt GR, Adelman CA, Petrini JHJ, Ramanathan Y, Singh B.

Squamous cell carcinoma-related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)-type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification. FAU - Huang, Guochang AU - Huang G AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Kaufman, Andrew J AU - Kaufman AJ AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Ryan, Russell J H AU - Ryan RJH AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Romin, Yevgeniy AU - Romin Y AD - Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Huryn, Laryssa AU - Huryn L AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Bains, Sarina AU - Bains S AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Manova-Todorova, Katia AU - Manova-Todorova K AD - Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Morris, Patricia L AU - Morris PL AD - Population Council and The Rockefeller University, New York, New York, United States of America. FAU - Hunnicutt, Gary R AU - Hunnicutt GR AUID- ORCID: 0000-0001-7600-8947 AD - Population Council and The Rockefeller University, New York, New York, United States of America. FAU - Adelman, Carrie A AU - Adelman CA AD - Department of Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Petrini, John H J AU - Petrini JHJ AD - Department of Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. FAU - Ramanathan, Y AU - Ramanathan Y AD - Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.