Fbxo41 Promotes Disassembly of Neuronal Primary Cilia

Neuronal primary cilia are signaling organelles with crucial roles in brain development and disease. Cilia structure is decisive for their signaling capacities but the mechanisms regulating it are poorly understood. We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit tha...

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Bibliographic Details
Published in:Scientific reports 2019-06, Vol.9 (1), p.8179-8179, Article 8179
Main Authors: King, Cillian R., A. A. Quadros, Ana R., Chazeau, Anaël, Saarloos, Ingrid, van der Graaf, Anne Jolien, Verhage, Matthijs, Toonen, Ruud F.
Format: Article
Language:English
Subjects:
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13/106
13/109
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14/1
14/19
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631/378/2571
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Actin
Animals
Centrioles
Centrioles - genetics
Centrosome - metabolism
Centrosomes
Cilia
Cilia - genetics
Cilia - metabolism
Cytoskeleton
Esters
F-Box Proteins - genetics
Hedgehog protein
Humanities and Social Sciences
Humans
Mice
multidisciplinary
Neurons - metabolism
NIH 3T3 Cells
Organelles
Phorbol esters
Science
Science (multidisciplinary)
Signal transduction
Signal Transduction - genetics
Yeast
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Summary:Neuronal primary cilia are signaling organelles with crucial roles in brain development and disease. Cilia structure is decisive for their signaling capacities but the mechanisms regulating it are poorly understood. We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit that targets to neuronal centrioles where its accumulation promotes disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical ciliary pathway. Fbxo41 targeting to centrioles requires its Coiled-coil and F-box domains. Levels of Fbxo41 at the centrioles inversely correlate with neuronal cilia length, and mutations that disrupt Fbxo41 targeting or assembly into SCF-complexes also disturb its function in cilia disassembly and signaling. Fbxo41 dependent cilia disassembly in mitotic and post-mitotic cells requires rearrangements of the actin-cytoskeleton, but requires Aurora A kinase activation only in mitotic cells, highlighting important mechanistical differences controlling cilia size between mitotic and post-mitotic cells. Phorbol esters induce recruitment of overexpressed Fbxo41 to centrioles and cilia disassembly in neurons, but disassembly can also occur in absence of Fbxo41. We propose that Fbxo41 targeting to centrosomes regulates neuronal cilia structure and signaling capacity in addition to Fbxo41-independent pathways controlling cilia size.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-44589-2