Murine germ cell-specific disruption of Ift172 causes defects in spermiogenesis and male fertility

Abstract

Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. IFT172 is a component of the IFT complex. Global disruption of mouse Ift172 gene caused typical phenotypes of ciliopathy. Mouse Ift172 gene appears to translate two major proteins; the full-length protein is highly expressed in the tissues enriched in cilia and the smaller 130 kDa one is only abundant in the testis. In male germ cells, IFT172 is highly expressed in the manchette of elongating spermatids. A germ cell-specific Ift172 mutant mice were generated, and the mutant mice did not show gross abnormalities. There was no difference in testis/body weight between the control and mutant mice, but more than half of the adult homozygous mutant males were infertile and associated with abnormally developed germ cells in the spermiogenesis phase. The cauda epididymides in mutant mice contained less developed sperm that showed significantly reduced motility, and these sperm had multiple defects in ultrastructure and bent tails. In the mutant mice, testicular expression levels of some IFT components, including IFT20, IFT27, IFT74, IFT81 and IFT140, and a central apparatus protein SPAG16L were not changed. However, expression levels of ODF2, a component of the outer dense fiber, and AKAP4, a component of fibrous sheath, and two IFT components IFT25 and IFT57 were dramatically reduced. Our findings demonstrate that IFT172 is essential for normal male fertility and spermiogenesis in mice, probably by modulating specific IFT proteins and transporting/assembling unique accessory structural proteins into spermatozoa.

Preliminary investigation of the function of hsa_circ_0049356 in nonobstructive azoospermia patients

“…Among the downstream mRNAs, several targets were previously demonstrated to be associated with different periods of sperm generation. Zhang et al found that IFT25 and IFT57 were reduced in Ift172 mutant mice, which can affect the structural protein transport during the spermatogenesis phase (Zhang et al., 2020). Moretti et al suggested that TBL1XR1 interacts with SLY, which is closely associated with the master genes of spermatid transcriptional regulation and further modulated the chromatin remodelling process (Moretti et al., 2017).…”

Sperm Differentiation: The Role of Trafficking of Proteins

“…Ift88 -/mice display impaired spermiogenesis with spermatids carrying several anomalies [29]. Other intraflagellar transport genes were similarly selected during evolution [27] and are essential during spermiogenesis, including Ift20 [30], Ift25 [31], Ift27 [32], Ift74 [33], Ift140 [34] and Ift172 [35].…”

“…IFTA interacts with dynein motors and IFTB with kinesin motors to transport proteins along microtubules. IFT transport is essential for mammalian spermiogenesis [29][30][31][32][33][34][35].…”

Some thoughts about intraflagellar transport in reproduction

“…The tissue‐/cell‐specific knockout technique is a game‐changer. Using the Stra8‐cre transgenic mice, we successfully disrupted Ift20, Ift25, Ift27, Ift140, Ift74, Ift81 , and Ift172 (Liu et al, 2017; Qu et al, 2020; Shi et al, 2019; Z. Zhang et al, 2016; Y. Zhang et al, 2017, 2018; S. Zhang et al, 2020) in male germ cells. All these mutant mice were grossly normal, but spermiogenesis and fertility were affected.…”

“…Each IFT component might be responsible for carrying specific cargo proteins for sperm flagella formation. For example, IFT74 and IFT81 are likely more important for carrying tubulin for the sperm core axoneme structure formation (Shi et al, 2019; S. Zhang et al, 2020). IFT25 and IFT27 are likely uninvolved in core axoneme formation, but they are more likely to carry proteins for assembling sperm accessory structures (Liu et al, 2017; Y. Zhang et al, 2017).…”