Emerging mechanistic understanding of cilia function in cellular signalling

Hilgendorf, Keren I.; Myers, Benjamin R.; Reiter, Jeremy F.

doi:10.1038/s41580-023-00698-5

Cited by 10 publications

(5 citation statements)

References 254 publications

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“…3d ). Localization of PKA-Cα to primary cilia aligns with previous findings on the role of this subunit in the regulation of Hedgehog (Hh) signaling in the cilium, where it phosphorylates and inactivates GLI2/3 transcription factors to repress expression of Hh target genes 6,29 . Further, TAK1 and TAB2 were recently identified in cilia proteomic studies 30,31 .…”

Section: Resultssupporting

confidence: 86%

“…This signaling crosstalk include, but may not be limited to, the canonical branch of TGFB/BMP signaling and Hh signaling ( Fig 5n ). In support of this model, which emphasizes the intricate interplay among ciliary pathway modules in regulating developmental signaling outcomes, TAK1 has been shown to bind and regulate the activity of R-SMADs 41 , and upstream of TAK1, PKA-Cα downregulates Hh signaling by processing GLI2/3 transcription factors within the ciliary compartment 29 . Conversely, inhibiting GLI1 in the Hh pathway was shown to activate the TAK1-JNK1/2 signaling axis 42 , introducing another layer of interaction between Hh and TAK1 signaling systems.…”

Section: Discussionmentioning

confidence: 88%

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TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

Doganli,

Baird,

Ali

et al. 2024

Preprint

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Transforming Growth Factor-Beta-Activated Kinase 1 (TAK1/MAP3K7), along with its upstream regulators TAK1-Binding Protein 2 (TAB2) and the catalytic alpha-subunit of Protein Kinase A (PKA-Cα/PRKACA), has been identified as a pivotal player in regulation of developmental processes. Haploinsufficiency of TAB2 causes Congenital Heart Disease (CHD) and rare variants in PKA-Cα and TAK1 cause cardioacrofacial dysplasia (CAFD), and Frontometaphyseal Dysplasia (FMD) and cardiospondylocarpofacial syndrome (CSCFS), respectively, rare multisystem syndromes, where CHD may appear in the clinical spectrum. We hypothesized that TAK1 plays a significant role in heart development and CHD and addressed this by genetic analysis in CHD patient cohorts and experiments in cell and animal models. Exome sequencing data from 1,471 CHD patients with extracardiac anomalies (syndromic CHD, sCHD), 2,405 patients with nonsyndromic CHD (nsCHD) and 45,082 controls showed increased burden of rare TAB2 and TAK1 variants in sCHD, but not in nsCHD. Detailed characterization of tak1-/- and tab2-/- zebrafish mutants revealed cardiac defects (dilated atrium, trabeculation defects, tachycardia and reduced contractility) as well as extracardiac developmental anomalies. RNA sequencing of tak1-/- mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. Experiments with cell cultures and analysis of zebrafish larvae and gastruloids indicated that TAK1 via TAB2 and PKA-Cα is activated at the primary cilium during cardiomyogenesis and that TAK1 activation at this site is enhanced by cardiomyogenic signaling molecules, including ligands of the TGFB/BMP superfamily. Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or administration of small molecule inhibitors targeting TAK1 inhibited ciliary signaling and cardiomyocyte differentiation in vitro, while FMD-causing mutations in TAK1 reduced its ciliary localization. In conclusion, our data establishes a central role for TAK1 and its upstream regulators in cardiac development and syndromic CHD, coordinated via the primary cilium.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 88%

TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

Doganli,

Baird,

Ali

et al. 2024

Preprint

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“…Once localized, these proteins appear to be remarkably stable and exhibit limited turnover or diffusion (van der Burght et al, 2020; van Krugten et al, 2022); this stability may account for the maintenance of glycerol responses without continuous IFT. However, IFT plays a critical role in regulating responses to diverse ligands including the Hedgehog morphogen across species, suggesting that the contribution of IFT may be distinct for different stimuli and cell types (Bruggeman et al, 2022; Hilgendorf et al, 2024; Hirano et al, 2017; Mukhopadhyay et al, 2010; Nachury, 2018; Werner et al, 2024). Identification of the glycerol receptor and characterization of its localization upon acute and chronic inhibition of IFT will be necessary to address the underlying mechanisms in ASH.…”

Section: Discussionmentioning

confidence: 99%

Differential modulation of sensory response dynamics by cilia structure and intraflagellar transport within and across chemosensory neurons

Philbrook,

O’Donnell,

Grunenkovaite

et al. 2024

Preprint

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Sensory neurons contain morphologically diverse primary cilia that are built by intraflagellar transport (IFT) and house sensory signaling molecules. Since both ciliary structural and signaling proteins are trafficked via IFT, it has been challenging to decouple the contributions of IFT and cilia structure to neuronal responses. By acutely inhibiting IFT without altering cilia structure and vice versa, here we describe the differential roles of ciliary trafficking and sensory ending morphology in shaping chemosensory responses in C. elegans. We show that a minimum cilium length but not continuous IFT is necessary for a subset of responses in the ASH nociceptive neurons. In contrast, neither cilia nor continuous IFT are necessary for odorant responses in the AWA olfactory neurons. Instead, continuous IFT differentially modulates response dynamics in AWA. Upon acute inhibition of IFT, cilia-destined odorant receptors are shunted to ectopic branches emanating from the cilia base. Spatial segregation of receptors in these branches from a cilia-restricted regulatory kinase results in odorant desensitization defects, highlighting the importance of precise organization of signaling molecules at sensory endings in regulating response dynamics. We also find that adaptation of AWA responses upon repeated exposure to an odorant is mediated by IFT-driven removal of its cognate receptor, whereas adaptation to a second odorant is regulated via IFT-independent mechanisms. Our results reveal unexpected complexity in the contribution of IFT and cilia organization to the regulation of responses even within a single chemosensory neuron type, and establish a critical role for these processes in the precise modulation of olfactory behaviors.

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“…PC provide essential contributions to intercellular communication by housing numerous cell surface receptors and their downstream effectors ( Hilgendorf et al, 2024 ; Mukhopadhyay and Rohatgi, 2014 ). Consistent with this functionality, the SHH pathway signal transducer SMO localizes to the ciliary membrane and communicates with GLI transcriptional effectors as they cycle through the PC ( Arensdorf et al, 2016 ; Kong et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length

Ansari,

Dillard,

Zhang

et al. 2024

Journal of Cell Biology

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Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4−/− mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling.

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Emerging mechanistic understanding of cilia function in cellular signalling

Cited by 10 publications

References 254 publications

TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

Differential modulation of sensory response dynamics by cilia structure and intraflagellar transport within and across chemosensory neurons

Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length

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