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- Title
Golgi associated RAB2 interactor protein family contributes to murine male fertility to various extents by assuring correct morphogenesis of sperm heads.
- Authors
Wang, Haoting; Iida-Norita, Rie; Mashiko, Daisuke; Pham, Anh Hoang; Miyata, Haruhiko; Ikawa, Masahito
- Abstract
Sperm heads contain not only the nucleus but also the acrosome which is a distinctive cap-like structure located anterior to the nucleus and is derived from the Golgi apparatus. The Golgi Associated RAB2 Interactors (GARINs; also known as FAM71) protein family shows predominant expression in the testis and all possess a RAB2-binding domain which confers binding affinity to RAB2, a small GTPase that is responsible for membrane transport and vesicle trafficking. Our previous study showed that GARIN1A and GARIN1B are important for acrosome biogenesis and that GARIN1B is indispensable for male fertility in mice. Here, we generated KO mice of other Garins, namely Garin2, Garin3, Garin4, Garin5a, and Garin5b (Garin2-5b). Using computer-assisted morphological analysis, we found that the loss of each Garin2-5b resulted in aberrant sperm head morphogenesis. While the fertilities of Garin2-/- and Garin4-/- males are normal, Garin5a-/- and Garin5b-/- males are subfertile, and Garin3-/- males are infertile. Further analysis revealed that Garin3-/- males exhibited abnormal acrosomal morphology, but not as severely as Garin1b-/- males; instead, the amounts of membrane proteins, particularly ADAM family proteins, decreased in Garin3 KO spermatozoa. Moreover, only Garin4 KO mice exhibit vacuoles in the sperm head. These results indicate that GARINs assure correct head morphogenesis and some members of the GARIN family function distinctively in male fertility. Author summary: Approximately 5% of males exhibit infertility, which has become a significant problem worldwide. One major reason for male infertility is teratozoospermia, characterized by spermatozoa with abnormal morphology. However, the genetic cause of teratozoospermia is largely unknown. In our previous study, we found two proteins belonging to the Golgi associated RAB2 interactor (GARIN) protein family are responsible for sperm acrosome biogenesis and mutation of each one of them causes globozoospermia in mice, which is a subset of teratozoospermia defined as spermatozoa that show round sperm heads with abnormal acrosome morphology. In this study, we generated knockout mice of each gene belonging to the Garin family. By applying elliptic Fourier descriptors (EFDs) and principal component (PC) analysis on sperm heads, we demonstrated that GARINs are all responsible for correct sperm head morphogenesis. GARINs are all conserved in humans, and expanding the understanding of GARINs potentially contributes to the elucidation of human male infertility.
- Subjects
FERTILITY; SPERMATOZOA; MORPHOGENESIS; BIOLOGICAL transport; INFERTILITY; MALE infertility; GOLGI apparatus; MEMBRANE proteins
- Publication
PLoS Genetics, 2024, Vol 20, Issue 6, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1011337