Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Cornils, Astrid; Maurya, Ashish K.; Tereshko, Lauren; Kennedy, Julie; Brear, Andrea G.; Prahlad, Veena; Blacque, Oliver E.; Sengupta, Piali

doi:10.1371/journal.pgen.1006325

Cited by 23 publications

(23 citation statements)

References 98 publications

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“…At days 4 and 8 of adulthood for MKS-6 ("MKS module" TZ protein), and day 4 for NPHP-4 ("NPHP module" TZ protein), ectopic TZ protein localisation is reduced compared to 1-day-old adults (Figs 5A and B, and EV5A and B). While perhaps surprising, our findings are consistent with those of Cornils and colleagues [76], who reported an improvement in cilia morphology (TZ was not looked at) for some hypomorphic IFT mutants during ageing, a process requiring IFT. However, we also discovered a significant, age-dependent difference in the ability of ts-che-3 mutant animals to restore their ciliary structures when shifted from restrictive to permissive temperature (Figs 5A and B, and EV5A and B).…”

Section: Cilia Repair Potential Decreases In Older Animalssupporting

confidence: 92%

Role for intraflagellar transport in building a functional transition zone

Jensen

Lambacher

et al. 2018

EMBO Reports

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Genetic disorders caused by cilia dysfunction, termed ciliopathies, frequently involve the intraflagellar transport (IFT) system. Mutations in IFT subunits—including IFT‐dynein motor DYNC2H1—impair ciliary structures and Hedgehog signalling, typically leading to “skeletal” ciliopathies such as Jeune asphyxiating thoracic dystrophy. Intriguingly, IFT gene mutations also cause eye, kidney and brain ciliopathies often linked to defects in the transition zone (TZ), a ciliary gate implicated in Hedgehog signalling. Here, we identify a C. elegans temperature‐sensitive (ts) IFT‐dynein mutant (che‐3; human DYNC2H1) and use it to show a role for retrograde IFT in anterograde transport and ciliary maintenance. Unexpectedly, correct TZ assembly and gating function for periciliary proteins also require IFT‐dynein. Using the reversibility of the novel ts‐IFT‐dynein, we show that restoring IFT in adults (post‐developmentally) reverses defects in ciliary structure, TZ protein localisation and ciliary gating. Notably, this ability to reverse TZ defects declines as animals age. Together, our findings reveal a previously unknown role for IFT in TZ assembly in metazoans, providing new insights into the pathomechanism and potential phenotypic overlap between IFT‐ and TZ‐associated ciliopathies.

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Section: Cilia Repair Potential Decreases In Older Animalssupporting

confidence: 92%

Role for intraflagellar transport in building a functional transition zone

Jensen

Lambacher

et al. 2018

EMBO Reports

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“…Primary cilia and aging have been investigated by several studies. Cornils et al 40 reported the increased variability in ASI cilia length as animal aged. Recently, it was reported that primary cilia length are frequently changed in aging‐related and neurodegenerative disorders 41 .…”

Section: Discussionmentioning

confidence: 99%

Ciliary IFT80 is essential for intervertebral disc development and maintenance

Yang

Han

et al. 2020

FASEB j.

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The intervertebral disc degeneration (IVDD)-related diseases occur in more than 90% of the population older than 50 years. Owing to the lack of understanding of the cellular mechanisms involved in IVDD formation effective treatment options are still unavailable. Primary cilia are microtubule-based organelles that play important roles in the organ development. Intraflagellar transport (IFT) proteins are essential for the assembly and bidirectional transport within the cilium. Role of cilia and IFT80 protein in intervertebral disc (IVD) development, maintenance, and degeneration are largely unknown. Using cilia-GFP mice, we found presence of cilia on growth plate (GP), cartilage endplate (EP) annulus fibrosus (AF), and nucleus pulposus (NP) with varying ciliary length. Cilia length in NP and AF during IVDD were significantly decreased. However, cilia numbers increased by 63% in AF during repair. Deletion of IFT80 in type II collagen-positive cells resulted in cilia loss in GP and EP, and disrupted IVD structure with disorganized and decreased GP, EP, and internal AF (IAF), and less compact and markedly decreased gel-like matrix in the NP. Deletion of IFT80 in type I collagen-positive cells led to a disorganized outer AF (OAF) with thinner, loosened, and disconnected fiber alignment. Mechanistic analyses showed that loss of IFT80 caused a significant increase in cell apoptosis in the IVD, and a marked decrease in expression of chondrogenic markers -type II collagen, sox9, aggrecan, and hedgehog (Hh) signaling components, including Gli1 and Patch1 in the IVD of IFT80 fl/fl ; Col2-creERT mice, and Gli1 and Patch1 expression in the OAF of IFT80 fl/fl ; Col1-creERT mice. Interestingly, Smoothened agonist-SAG rescued OAF cell proliferation and osteogenic differentiation. Our findings demonstrate that ciliary IFT80 is important for the maintenance of IVD cell organization and function through regulating the cell survival and Hh signaling. K E Y W O R D S annulus fibrosus, IFT80, intervertebral disc degeneration, nucleus pulposus, primary cilia 6742 | LI et aL.

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“…While degenerative ciliary phenotypes may become progressively worse with time, a developmental phenotype may improve with time in certain mutant backgrounds. A recent publication may already have showed evidence of this, describing structural and functional time-dependent recovery of sensory cilia from young adulthood to middle age in C. elegans hypomorphic mutants previously known for axonemal structural defects (Barr, 2016;Cornils et al, 2016). Similarly, Drosophila mutants that lack TZlocalizing MKS proteins and show axonemal structural defects in larval development recover in adulthood (Pratt et al, 2016).…”

Section: Wild-type Cem and Il2 Tzs Have Incomplete Dmts And Smts Withmentioning

confidence: 99%

Cell type-specific structural plasticity of the ciliary transition zone inC. elegans

Akella

Silva

Morsci³

et al. 2018

Preprint

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Running Title: Transition zone structure can change on cilia type. Both cases result in structural TZ intermediates different from TZ in adult cilia. In CEM cilia, axonemal extension and maturation occurs concurrently with TZ structural maturation. Conclusions and SignificanceOur work extends the current model to include the structural plasticity of metazoan transition zone, which can be structurally delayed, maintained or remodeled in cell typespecific manner.

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Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Cited by 23 publications

References 98 publications

Role for intraflagellar transport in building a functional transition zone

Role for intraflagellar transport in building a functional transition zone

Ciliary IFT80 is essential for intervertebral disc development and maintenance

Cell type-specific structural plasticity of the ciliary transition zone inC. elegans

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