CABYR is essential for fibrous sheath integrity and progressive motility in mouse spermatozoa

Young, Sam; Miyata, Haruhiko; Satouh, Yuhkoh; Aitken, R. John; Baker, Mark A.; Ikawa, Masahito

doi:10.1242/jcs.193151

Cited by 45 publications

(40 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility is that IFT25/IFT27 does play a role in assembling the core axoneme structure of sperm, which is different from their roles the somatic cells where they do not modulate ciliogenesis. Another possibility is that the defects of the core axoneme structure are secondary to the defects of the accessory structures, which was reported in the CABYR mutant mice (Young et al, 2016), in which the axoneme defect was caused by defects of fibrous sheath.…”

Section: Discussionmentioning

confidence: 99%

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

Zhang

Liu

et al. 2017

Developmental Biology

View full text Add to dashboard Cite

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. In mice, mutations in IFT proteins have been shown to cause several ciliopathies including retinal degeneration, polycystic kidney disease, and hearing loss. However, little is known about its role in the formation of the sperm tail, which has the longest flagella of mammalian cells. IFT27 is a component of IFT-B complex and binds to IFT25 directly. In mice, IFT27 is highly expressed in the testis. To investigate the role of IFT27 in male germ cells, the floxed Ift27 mice were bred with Stra8-iCre mice so that the Ift27 gene was disrupted in spermatocytes/spermatids. The Ift27:Stra8-iCre mutant mice did not show any gross abnormalities, and all of the mutant mice survive to adulthood. There was no difference between testis weight/body weight between controls and mutant mice. All adult homozygous mutant males examined were completely infertile. Histological examination of the testes revealed abnormally developed germ cells during the spermiogenesis phase. The epididymis contained round bodies of cytoplasm. Sperm number was significantly reduced compared to the controls and only about 2% of them remained significantly reduced motility. Examination of epididymal sperm by light microscopy and SEM revealed multiple morphological abnormalities including round heads, short and bent tails, abnormal thickness of sperm tails in some areas, and swollen tail tips in some sperm. TEM examination of epididymal sperm showed that most sperm lost the “9+2” axoneme structure, and the mitochondria sheath, fibrous sheath, and outer dense fibers were also disorganized. Some sperm flagella also lost cell membrane. Levels of IFT25 and IFT81 were significantly reduced in the testis of the conditional Ift27 knockout mice, and levels of IFT20, IFT74, and IFT140 were not changed. Sperm lipid rafts, which were disrupted in the conditional Ift25 knockout mice, appeared to be normal in the conditional Ift27 knockout mice. Our findings suggest that like IFT25, IFT27, even though not required to ciliogenesis in somatic cells, is essential for sperm flagella formation, sperm function, and male fertility in mice. IFT25 and IFT27 control sperm formation/function through many common mechanisms, but IFT25 has additional roles beyond IFT27.

show abstract

Section: Discussionmentioning

confidence: 99%

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

Zhang

Liu

et al. 2017

Developmental Biology

View full text Add to dashboard Cite

show abstract

“…Mutations in multiple genes in mouse models have been identified that disrupt the formation of the flagellum or the function of the flagellum (9,10). For example, mutations in Akap4, Tekt3, Tekt4, and Cabyr in mice lead to structural defects in the flagellum, whereas mutations in CatSper1, Pgk2, Gapdhs, and Ldhc lead to functional defects in the flagellum, some of which cause defective metabolism or glycolysis (11)(12)(13)(14)(15)(16)(17)(18). In men, mutations in CATSPER, DNAH1, DNAH11, and TEKT2 have been shown to lead to asthenozoospermia and sterility (19)(20)(21)(22).…”

Section: Significancementioning

confidence: 99%

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa

Castaneda

Hua

Miyata

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the "9+2" microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction. T-Complex-Associated-Testis-Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids and protein localized to the flagellum. TCTE1 is 498 aa in length with a leucine rich repeat domain at the C terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1-null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1-null sperm demonstrate a significant decrease of ATP, which is used by dynein motors to generate the bending force of the flagellum. These data provide a link to defining the molecular intricacies required for axoneme function, sperm motility, and male fertility. male infertility | asthenozoospermia | glycolysis | mutant mouse | testis-specific gene F lagella are ancient, analogous cellular structures used for locomotion and as sensory organelles present in all three domains of life (bacteria, archaea, and eukaryotes). The advantages conferred by this organelle are highlighted by the flagella's apparent independent evolution in all three domains (1-3). Of all of the different flagella present among eukaryotes, flagella attached to gametes play a critical function in uniting gametes for fertilization and the perpetuation of a species. Mammalian spermatozoa have a specialized flagellum that contains a midpiece, principal piece, and end piece with the axoneme running along the entire length (4). The flagellum equips sperm with the capability to deliver half of the male's genetic material to the female gamete, the oocyte. In addition to flagella, eukaryotes contain another related structure called cilia. The defining feature of flagella and cilia is the axoneme, the "9+2" microtubule arraignment of two central pairs of microtubules surrounded by nine pairs of microtubule doublets (5). The microtubule motor dynein is anchored to the outer microtubules and responsible for generating the force required to produce the beating pattern of flagella and cilia (6). The force generated by dynein causes sliding of the microtubules among each other; however, the nexin complex anchors the microtubules in place. The nexin complex [or nexin-dynei...

show abstract

“…In vitro research showed that CABYR might play a role in capacitation . However, CRISPR‐Cas9‐generated Cabyr KO male mice were severely subfertile due to significantly reduced sperm motility and electron microscopy of the KO spermatozoa showed disorganized fibrous sheaths …”

Section: Crispr/cas9 and Reproductionmentioning

confidence: 99%

Revolutionizing male fertility factor research in mice by using the genome editing tool CRISPR/Cas9

Abbasi

Miyata

Ikawa

2017

Reprod Medicine & Biology

Self Cite

View full text Add to dashboard Cite

BackgroundReproductive research is quintessential in understanding not only the cause of infertility, but also for creating family planning tools. The knockout (KO) system approach is conducive to discovering genes that are essential for fertility in mice. However, in vivo research has been limited due to its high cost and length of time needed to establish KO mice.MethodsThe mechanisms behind the CRISPR/Cas9 system and its application in investigating male fertility in mice are described by using original and review articles.ResultsThe CRISPR/CAS9 SYSTEM has enabled researchers to rapidly, efficiently, and inexpensively produce genetically modified mice to study male fertility. Several genes have been highlighted that were found to be indispensable for male fertility by using the CRISPR/Cas9 system, as well as more complicated gene manipulation techniques, such as point mutations, tag insertions, and double knockouts, which have become easier with this new technology.ConclusionIn order to increase efficiency and usage, new methods of CRISPR/Cas9 integration are being developed, such as electroporation and applying the system to embryonic stem cells. The hidden mysteries of male fertility will be unraveled with the help of this new technology.

show abstract

CABYR is essential for fibrous sheath integrity and progressive motility in mouse spermatozoa

Cited by 45 publications

References 50 publications

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa

Revolutionizing male fertility factor research in mice by using the genome editing tool CRISPR/Cas9

Contact Info

Product

Resources

About