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Nexin-Dynein regulatory complex component DRC7 but not FBXL13 is required for sperm flagellum formation and male fertility in mice

Morohoshi, Akane 大阪大学

2020.01.21

概要

Cilia and flagella are evolutionarily-conserved microtubule-based organelles extending from
the surface of many cell types and are used for sensing and motility [1–3]. Defects in the formation or motility of these organelles are associated with human diseases such as impaired
mucociliary clearance and recurrent respiratory infections, which is called primary ciliary dyskinesia (PCD) [4]. The central component of motile cilia and flagella is the axoneme, the ‘9+2’
microtubule arrangement that consists of a central pair (CP) of two singlet microtubules surrounded by nine outer microtubule doublets (Fig 1A) [5,6]. Each doublet microtubule is composed of an A-tubule and a B-tubule. In addition to the microtubule arrangement, the
axoneme contains several accessory structures such as inner dynein arms (IDAs), outer dynein
arms (ODAs), radial spokes (RSs), and the Nexin-Dynein Regulatory Complex (N-DRC). The
IDAs and ODAs are motor complexes attached to the A-tubule and drive axoneme beating by
sliding the neighboring doublet microtubules in an ATP dependent manner [7,8]. The RSs
extend from the doublet microtubules towards the CP and mediate signal transduction
between the CP and the dynein arms [9].
The N-DRC is a large complex that links the A-tubule of one doublet to the B-tubule of the
adjacent doublet [10–12]. In the unicellular flagellate Chlamydomonas reinhardtii, 11 distinct
subunits that compose the N-DRC have been identified [10,13,14]. Further studies using Chlamydomonas mutants revealed that the N-DRC plays critical roles in regulating flagellar motility [15–17]. Involvement of N-DRC in regulating flagellar motility has also been clarified in
the flagellate protozoa Trypaosoma brucei [18–20]. The N-DRC components are conserved
evolutionarily from Chlamydomonas and Trypanosoma to humans and several studies have
shown a link between DRC disruptions and ciliary motility defects in vertebrates. For example,
gas8 (drc4) knockdown leads to impaired cilia motility in zebrafish embryos [21]. Further,
mutations in CCDC164 (DRC1), CCDC65 (DRC2), and GAS8 have been found in PCD
patients [22–24]. In mouse models, mutations in Gas8 and Lrrc48 (Drc3) phenocopy PCD
patients [25,26].
In addition to ciliary motility defects, PCD patients can exhibit infertility due to abnormal
flagellar movement of the spermatozoa. Although detailed morphology and motility of the
spermatozoa were not described, an asthenozoospermia patient with a mutation in GAS8 was
reported [27]. In mice, it was reported that Lrrc48 mutant males were infertile in addition to
displaying abnormal ciliary motility [26]. Further, Iqcg (Drc9) KO male mice were infertile due
to severe defects in flagellar formation and immotility of spermatozoa [28]. ...

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