Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly1

Abstract

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.

MRG15 is required for pre-mRNA splicing and spermatogenesis

“…In addition, at least Mtap2, Eif4g3, Usp2, Mtap7, Ace, and Tex14 are known to play a role in male fertility (29)(30)(31)(32)(33)(34), and overexpression of Spata17 and Rpgr leads to male infertility (35,36). Therefore, the infertility in the Mrg15 cKO mice could be secondary to alterations in the levels of these proteins.…”

Mechanisms of mammalian ciliary motility: Insights from primary ciliary dyskinesia genetics

“…Ultrastructural analysis of cilia from two patients revealed a variety of defects, including absence of dynein arms, absence of the central pair, and absence of nexin links. In addition, over-expression of RPGR in transgenic mice results in male infertility (Brunner et al, 2008). Flagellar defects range from disorganization of the midpiece, the outer dense fibers, and the fibrous sheath in mice with low copy numbers to complete absence of flagella in the presence of extensive over-expression.…”

The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo

“…The disorder is characterized by night blindness, progressive loss of the peripheral visual field leading to complete blindness [2]. Some retinitis pigmentosa patients manifest more ciliopathy phenotypes as abnormal sperm development, respiratory tract infections and hearing defects [3][4][5].…”

“…One of the two main isoforms is the widely expressed RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] consisting of 19 exons encoding a protein of 815 amino acids where exons 2-11 comprise the RLD [10]. A carboxy-terminal CAAX box, specific for geranylgeranylation, was shown to be essential for the localization and function of the protein [11].…”