Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly

• Published in: Biology of reproduction Vol. 79; no. 4; pp. 608 - 617
• Main Authors: Brunner, Sandra, Colman, Dvora, Travis, Alexander J, Luhmann, Ulrich F.O, Shi, Wei, Feil, Silke, Imsand, Coni, Nelson, Jacquelyn, Grimm, Christian, Rülicke, Thomas, Fundele, Reinald, Neidhardt, John, Berger, Wolfgang
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction, Inc 01.10.2008; Society for the Study of Reproduction
• Subjects: Animals; Biologi; Biological and medical sciences; Biological Transport - genetics; Biology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - physiology; Eye Proteins - genetics; Eye Proteins - metabolism; Eye Proteins - physiology; flagellum; Gene Dosage - physiology; Gynecology. Andrology. Obstetrics; infertility; Infertility, Male - genetics; Male; Male genital diseases; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; NATURAL SCIENCES; NATURVETENSKAP; Non tumoral diseases; sperm; Sperm Tail - metabolism; Sperm Tail - physiology; Sperm Tail - ultrastructure; spermatogenesis; Spermatogenesis - genetics; Spermatozoa - abnormalities; testis; Testis - cytology; Up-Regulation - physiology; Spermatozoa; Retinopathy; Retinitis pigmentosa; Spermatogenesis; Rodentia; Flagellum; Sterile; sperm; testis; Germinal cell; Fecundation; Testicle; infertility; Male genital system; In vitro; Genetic disease; Eye disease; Vertebrata; Mammalia; Mouse
• ISSN: 0006-3363; 1529-7268; 1529-7268
• DOI: 10.1095/biolreprod.107.067454

Male infertility is one possible consequence of a group of disorders arising from dysfunction of cilia. Ciliopathies include primary ciliary dyskinesia, polycystic kidney disease, Usher syndrome, nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome as well as some forms of retinal degenerations. Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR) are best known for leading to retinal degeneration but have also been associated with ciliary dysfunctions affecting other tissues. To further study the involvement of RPGR in ciliopathies, transgenic mouse lines overexpressing RPGR were generated. Animals carrying the transgene in varying copy numbers were investigated. We found that infertility due to aberrant spermatozoa correlated with increased copy numbers. In animals with moderately increased gene copies of Rpgr, structural disorganization in the flagellar midpiece, outer dense fibers, and fibrous sheath was apparent. In contrast, in animals with high copy numbers, condensed sperm heads were present, but the flagellum was absent in the vast majority of spermatozoa, although early steps of flagellar biogenesis were observed. This complexity of defects in flagellar assembly suggests a role of RPGR in intraflagellar transport processes.