Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Overview

Journal Trends Cell Biol

Specialty Cell Biology

Date 2016 Oct 22

PMID 27765513

Citations 37

Authors

Mu He

Stephanie Agbu

Kathryn V Anderson

Affiliations

Soon will be listed here.

Abstract

The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilium-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control ciliary length and stability, and some have direct roles in mammalian Hh signal transduction. These studies highlight how integrated genetic and cell biological studies can define the molecular mechanisms that underlie cilium-associated health and disease.

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References

Scholey J . Kinesin-2: a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions. Annu Rev Cell Dev Biol. 2013; 29:443-69. DOI: 10.1146/annurev-cellbio-101512-122335. View

Niwa S, Nakajima K, Miki H, Minato Y, Wang D, Hirokawa N . KIF19A is a microtubule-depolymerizing kinesin for ciliary length control. Dev Cell. 2012; 23(6):1167-75. DOI: 10.1016/j.devcel.2012.10.016. View

Ou G, Blacque O, Snow J, Leroux M, Scholey J . Functional coordination of intraflagellar transport motors. Nature. 2005; 436(7050):583-7. DOI: 10.1038/nature03818. View

Huber C, Wu S, Kim A, Sigaudy S, Sarukhanov A, Serre V . WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia. Am J Hum Genet. 2013; 93(5):926-31. PMC: 3824112. DOI: 10.1016/j.ajhg.2013.10.007. View

Nozawa Y, Yao E, Lin C, Yang J, Wilson C, Gacayan R . Fused (Stk36) is a ciliary protein required for central pair assembly and motile cilia orientation in the mammalian oviduct. Dev Dyn. 2013; 242(11):1307-19. DOI: 10.1002/dvdy.24024. View

Barakeh D, Faqeih E, Anazi S, Al-Dosari M, Softah A, Albadr F . The many faces of KIF7. Hum Genome Var. 2016; 2:15006. PMC: 4785560. DOI: 10.1038/hgv.2015.6. View

Mukhopadhyay S, Wen X, Chih B, Nelson C, Lane W, Scales S . TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 2010; 24(19):2180-93. PMC: 2947770. DOI: 10.1101/gad.1966210. View

Ocbina P, Anderson K . Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn. 2008; 237(8):2030-8. PMC: 2702862. DOI: 10.1002/dvdy.21551. View

Tuson M, He M, Anderson K . Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development. 2011; 138(22):4921-30. PMC: 3201661. DOI: 10.1242/dev.070805. View

10.

Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C . Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet. 2013; 45(6):639-47. PMC: 3826256. DOI: 10.1038/ng.2613. View

11.

Ocbina P, Eggenschwiler J, Moskowitz I, Anderson K . Complex interactions between genes controlling trafficking in primary cilia. Nat Genet. 2011; 43(6):547-53. PMC: 3132150. DOI: 10.1038/ng.832. View

12.

Liew G, Ye F, Nager A, Murphy J, Lee J, Aguiar M . The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell. 2014; 31(3):265-278. PMC: 4255629. DOI: 10.1016/j.devcel.2014.09.004. View

13.

Waters A, Beales P . Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011; 26(7):1039-56. PMC: 3098370. DOI: 10.1007/s00467-010-1731-7. View

14.

Mourao A, Christensen S, Lorentzen E . The intraflagellar transport machinery in ciliary signaling. Curr Opin Struct Biol. 2016; 41:98-108. DOI: 10.1016/j.sbi.2016.06.009. View

15.

Li Y, Klena N, Gabriel G, Liu X, Kim A, Lemke K . Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015; 521(7553):520-4. PMC: 4617540. DOI: 10.1038/nature14269. View

16.

Yee L, Garcia-Gonzalo F, Bowie R, Li C, Kennedy J, Ashrafi K . Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling. PLoS Genet. 2015; 11(11):e1005627. PMC: 4635004. DOI: 10.1371/journal.pgen.1005627. View

17.

Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales S . The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell. 2013; 152(1-2):210-23. DOI: 10.1016/j.cell.2012.12.026. View

18.

El Hokayem J, Huber C, Couve A, Aziza J, Baujat G, Bouvier R . NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. J Med Genet. 2012; 49(4):227-33. DOI: 10.1136/jmedgenet-2011-100717. View

19.

Ye F, Breslow D, Koslover E, Spakowitz A, Nelson W, Nachury M . Single molecule imaging reveals a major role for diffusion in the exploration of ciliary space by signaling receptors. Elife. 2013; 2:e00654. PMC: 3736543. DOI: 10.7554/eLife.00654. View

20.

Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N . Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis. J Cell Biol. 1999; 145(4):825-36. PMC: 2133177. DOI: 10.1083/jcb.145.4.825. View