Actin polymerization controls cilia-mediated signaling

Drummond, Michael L.; Li, Mischa; Tarapore, Eric; Nguyen, Tuyen; Barouni, Baina J.; Cruz, Shaun; Tan, Kevin C.; Oro, Anthony E.; Atwood, Scott X.

doi:10.1083/jcb.201703196

Cited by 74 publications

(73 citation statements)

References 45 publications

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“…We showed that cilia elongation in OSNs of Joubert model validates importance of INPP5E to the cilia maintenance. However, as pointed earlier redistribution of PIP2 may induce aberrant remodeling of ciliary core by recruiting F-actin filaments thus contributing to cilia elongation (Madhivanan et al, 2015;Phua et al, 2017;Drummond et al, 2018). Ciliopathy associated with altered PIP2 distribution is not limited only by Joubert (INPP5E) syndrome but also occurs in a similar disease of oculo-cerebro-renal syndrome of Lowe (OCRL).…”

Section: Discussionmentioning

confidence: 91%

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov

Uytingco

Green

et al. 2018

Preprint

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Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5'phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs.Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation.However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level.These findings implicate phosphoinositide-dependent regulation of active Ca 2+ extrusion in OSNs whereby controlling the rate of sensory adaptation. Significance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

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Section: Discussionmentioning

confidence: 91%

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov

Uytingco

Green

et al. 2018

Preprint

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“…Interestingly, adhesion complexes such as those in focal adhesions are found in basal bodies, thus linking cilia with the actin cytoskeleton (Antoniades et al, 2014). Actin polymerization indeed affects primary cilium length and function (Kim et al, 2015;Drummond et al, 2018). Thus, a putative function of TRIP6 in ciliogenesis via a regulation of the actin cytoskeleton cannot be ruled out at this time.…”

Section: Discussionmentioning

confidence: 99%

Novel function of TRIP6, in brain ciliogenesis

Shukla

Urbánek

Frappart

et al. 2019

Preprint

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TRIP6, a member of the zyxin-family of LIM domain proteins, is a focal adhesion component. trip6 deletion in the mouse revealed, unexpectedly, in view of its ubiquitous expression, a function in the brain: ependymal and choroid plexus epithelial cells were poorly developed, carrying fewer and shorter cilia, and the mice developed hydrocephalus. TRIP6 disruption, via RNAi or inhibition of its homodimerization, in a choroid plexus epithelial cell line, confirmed its function in ciliogenesis. Zyxin-family members carry numerous protein interaction domains. In common with assembly of other multiprotein complexes, ciliogenesis may be facilitated by molecular assembly factors. Super-resolution microscopy demonstrated TRIP6 localization at the pericentriolar material and along the ciliary axoneme. The requirement for homodimerization which doubles its interaction sites, its punctate localization along the axoneme, and its co-localization with other cilia components suggest a scaffold/co-transporter function for TRIP6 in cilia. This is the first discovery of a protein assembly factor essential for mammalian ciliogenesis.

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“…We previously reported that loss of aPKC increased ciliogenesis and axoneme length, while suppressing HH pathway activation (Atwood et al 2013;Drummond et al 2018), suggesting that aPKC expression may dynamically regulate ciliogenesis. To further define the association between ciliogenesis and aPKC expression, we examined primary cilia upon aPKC overexpression.…”

Section: Apkc and Primary Cilia Mutually Inhibit Each Othermentioning

confidence: 99%

“…In this study, we find that loss of highly mutated cilia-associated genes disrupts primary cilia and attenuates HH pathway activation. Loss of primary cilia results in higher aPKC expression, which normally serves to restrict ciliogenesis (Drummond et al 2018). Expression of an aPKC isoform that only contains the kinase domain promotes HH signaling in the presence or absence of primary cilia and can confer resistance to vismodegib.…”

Section: Introductionmentioning

confidence: 99%

Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth

Nguyen

Jeon

Jhumkhawala

et al. 2020

Preprint

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Primary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog (HH)-driven cancers, how HH pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Here, we find that HH-driven basal cell carcinoma (BCC) accumulate mutations in the Alström and Usher syndrome genes in advanced and SMO inhibitorresistant tumors. Loss of Alström and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses ciliogenesis and HH signaling. Atypical protein kinase C iota/lambda (aPKC) is a GLI1 kinase with higher expression in advanced BCCs and we show that a constitutively active isoform drives HH pathway activity and mutually antagonizes primary cilia. Overexpression of the constitutively active aPKC variant can maintain HH pathway activity in the absence of primary cilia and can drive resistance to the SMO antagonist vismodegib regardless of cilia status. Finally, superficial BCCs display less primary cilia and higher aPKC expression, which is inversely correlated in nodular BCC subtypes. Our results suggest aPKC may serve as a biomarker for SMO inhibitor sensitivity and a target for clinical application.

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Actin polymerization controls cilia-mediated signaling

Cited by 74 publications

References 45 publications

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Novel function of TRIP6, in brain ciliogenesis

Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth

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