CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice

McKenzie, Casey W.; Craige, Branch; Kroeger, Tiffany V.; Finn, Rozzy; Wyatt, Todd A.; Sisson, Joseph H.; Pavlik, Jacqueline A.; Strittmatter, Lara; Hendricks, Gregory M.; Witman, George B.; Lee, Lance

doi:10.1091/mbc.e15-02-0121

Cited by 49 publications

(54 citation statements)

References 34 publications

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“…Deficiency of CA proteins can cause mammalian ciliopathies, including primary ciliary dyskinesia (PCD) (Teves et al, 2016;Horani and Ferkol, 2018). Mice deficient in either cfap54 or pcdp1, which encode conserved C1d proteins, show typical PCD symptoms, including ineffective mucus clearance, and/or male infertility, and hydrocephalus (Lee et al, 2008;DiPetrillo and Smith, 2010;McKenzie et al, 2015). Similarly, mutations of the C2b protein Hydin result in hydrocephalus caused by the loss of cilia-generated fluid flow in the brain ventricles (Lechtreck et al, 2008).…”

Section: Main Text Introductionmentioning

confidence: 99%

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Zhao

Dymek

et al. 2019

Preprint

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Running title: C1a-e-c supercomplex of motile cilia Summary Fu et al. use a wild-type vs. mutant comparison and cryo-electron tomography of Chlamydomonas flagella to identify central apparatus (CA) subunits and visualize their location in the native 3D CA structure. The study provides a better understanding of the CA and how it regulates ciliary motility. Abbreviations:BCCP, biotin-carboxyl-carrier-protein; CA, central apparatus; CCD, charge-coupled device; cryo-ET, cryo-electron tomography; DMT, doublet microtubule; FAP, flagellar associated protein; IDA, inner dynein arm; MS, mass spectrometry; N-DRC, nexin-dynein regulatory complex; ODA, outer dynein arm; PCD, primary ciliary dyskinesia; psu, peripheral subunit. AbstractNearly all motile cilia contain a central apparatus (CA) composed of two connected singletmicrotubules with attached projections that play crucial roles in regulating ciliary motility.Defects in CA assembly usually result in motility-impaired or paralyzed cilia, which in humans causes disease. Despite their importance, the protein composition and functions of the CA projections are largely unknown. Here, we integrated biochemical and genetic approaches with cryo-electron tomography to compare the CA of wild type Chlamydomonas with CA mutants.We identified a large (>2 MDa) complex, the C1a-e-c supercomplex, that requires the PF16 protein for assembly and contains the CA components FAP76, FAP81, FAP92, and FAP216. We localized these subunits within the supercomplex using nanogold-labeling and show that loss of any one of them results in impaired ciliary motility. These data provide insight into the subunit organization and three-dimensional (3D) structure of the CA, which is a prerequisite for understanding the molecular mechanisms by which the CA regulates ciliary beating. Despite many biochemical and structural studies of the CA (Witman et al., 1978; protein composition, 3D organization, and functional mechanism(s) of the CA in ciliary motility are not fully understood. Our recent mass spectrometry (MS) study compared the proteomes of Chlamydomonas wild-type and mutant axonemes, and identified 44 new candidate CA proteins assigned to the C1 or the C2 microtubule (Zhao et al., 2019).However, questions about the organization, assembly, and function of the CA and its projections remain, making the CA the structurally and functionally least understood axonemal complex to date.Here we combined biochemical, genetic, and structural analyses to investigate the protein composition and molecular organization of a group of interconnected CA projections, here termed the C1a-e-c supercomplex, in wild-type and CA mutants of Chlamydomonas. Sucrose gradient sedimentation and MS revealed that several CA proteins identified in this study, FAP76, FAP81, FAP92 and FAP216, are associated with the protein PF16, previously assigned to the C1 microtubule but not to a specific projection. Chlamydomonas mutants that lacked any of these proteins showed impaired motility. Structural comparisons of flagella from wild-ty...

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Section: Main Text Introductionmentioning

confidence: 99%

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Zhao

Dymek

et al. 2019

Preprint

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“…Deficiency of CA proteins can cause mammalian ciliopathies, including primary ciliary dyskinesia (PCD; Teves et al, 2016;Horani and Ferkol, 2018). Mice deficient in either Cfap54 or Pcdp1, which encode conserved C1d proteins, show typical PCD symptoms, including ineffective mucus clearance, male infertility, and hydrocephalus (Lee et al, 2008;DiPetrillo and Smith, 2010;McKenzie et al, 2015). Similarly, mutations of the C2b protein Hydin result in hydrocephalus caused by the loss of cilia-generated fluid flow in the brain ventricles (Lechtreck et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Zhao

Dymek

et al. 2019

Journal of Cell Biology

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Nearly all motile cilia contain a central apparatus (CA) composed of two connected singlet microtubules with attached projections that play crucial roles in regulating ciliary motility. Defects in CA assembly usually result in motility-impaired or paralyzed cilia, which in humans causes disease. Despite their importance, the protein composition and functions of the CA projections are largely unknown. Here, we integrated biochemical and genetic approaches with cryo-electron tomography to compare the CA of wild-type Chlamydomonas with CA mutants. We identified a large (2 MD) complex, the C1a-e-c supercomplex, that requires the PF16 protein for assembly and contains the CA components FAP76, FAP81, FAP92, and FAP216. We localized these subunits within the supercomplex using nanogold labeling and show that loss of any one of them results in impaired ciliary motility. These data provide insight into the subunit organization and 3D structure of the CA, which is a prerequisite for understanding the molecular mechanisms by which the CA regulates ciliary beating.

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“…In this scenario with divergent selective pressures promoting local adaptation, we identified the function of the genes with signatures of selection, with some of them related to the organization of the cytoskeleton (Figure ). Two of these genes, dynein heavy chain 3 ( DNAH3 ) and cilia and flagella associated protein 54 ( CFAP54 ), are involved in the assembly, function, motility and power stroke of flagella and cilia (Asai & Koonce, ; Carter, ; McKenzie et al, ). As with most other sponges, D. antarctica is a filter‐feeding sponge that relies on flagellar beating to modulate the inflow current for particle feeding, and therefore we suggest that the selection signatures in the previously mentioned genes might be related to divergent filtering abilities between the Bransfield Strait area and the central and southern WAP.…”

Section: Discussionmentioning

confidence: 99%

“…The significant 6.72% of the variance explained by this DAPC grouping (Table 4b) In this scenario with divergent selective pressures promoting local adaptation, we identified the function of the genes with signatures of selection, with some of them related to the organization of the cytoskeleton (Figure 4). Two of these genes, dynein heavy chain 3 (DNAH3) and cilia and flagella associated protein 54 (CFAP54), are involved in the assembly, function, motility and power stroke of flagella and cilia (Asai & Koonce, 2001;Carter, 2013;McKenzie et al, 2015).…”

Section: Signals Of Divergent Adaptive Selectionmentioning

confidence: 99%

Population substructure and signals of divergent adaptive selection despite admixture in the sponge Dendrilla antarctica from shallow waters surrounding the Antarctic Peninsula

Leiva

Taboada

Kenny³

et al. 2019

Molecular Ecology

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Antarctic shallow‐water invertebrates are exceptional candidates to study population genetics and evolution, because of their peculiar evolutionary history and adaptation to extreme habitats that expand and retreat with the ice sheets. Among them, sponges are one of the major components, yet population connectivity of none of their many Antarctic species has been studied. To investigate gene flow, local adaptation and resilience to near‐future changes caused by global warming, we sequenced 62 individuals of the sponge Dendrilla antarctica along the Western Antarctic Peninsula (WAP) and the South Shetlands (spanning ~900 km). We obtained information from 577 double digest restriction site‐associated DNA sequencing (ddRADseq)‐derived single nucleotide polymorphism (SNP), using RADseq techniques for the first time with shallow‐water sponges. In contrast to other studies in sponges, our 389 neutral SNPs data set showed high levels of gene flow, with a subtle substructure driven by the circulation system of the studied area. However, the 140 outlier SNPs under positive selection showed signals of population differentiation, separating the central–southern WAP from the Bransfield Strait area, indicating a divergent selection process in the study area despite panmixia. Fourteen of these outliers were annotated, being mostly involved in immune and stress responses. We suggest that the main selective pressure on D. antarctica might be the difference in the planktonic communities present in the central–southern WAP compared to the Bransfield Strait area, ultimately depending on sea‐ice control of phytoplankton blooms. Our study unveils an unexpectedly long‐distance larval dispersal exceptional in Porifera, broadening the use of genome‐wide markers within nonmodel Antarctic organisms.

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CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice

Cited by 49 publications

References 34 publications

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

Population substructure and signals of divergent adaptive selection despite admixture in the sponge Dendrilla antarctica from shallow waters surrounding the Antarctic Peninsula

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