Abstract
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.
Highlights
Primary cilia are antennae-like sensory organelles that project from the plasma membrane of a wide variety of cells, including neurons
In this study we show that Fbxo[41] assembles into an SCF complex, targets to neuronal centrioles, and its accumulation promotes disassembly of primary cilia
Endogenous Fbxo[41] located throughout the cytosol with distinctive enrichments in the soma, which co-localized with the pericentriolar protein Pericentrin (Fig. 1d), but Fbxo41-EGFP did not colocalize with several other somatic organelles (Supplementary Fig. S2)
Summary
Primary cilia are antennae-like sensory organelles that project from the plasma membrane of a wide variety of cells, including neurons They are composed of a microtubule-based core structure that elongates from a membrane-anchored modified centriole, the basal body[1]. Cilia length is highly dynamic[17] and cilia of olfactory neurons in C. elegans remodel in a sensory signaling-dependent manner[18] This implies the presence of machinery that senses extracellular cues and modulates ciliary architecture. The effect of Fbxo[41] in cilia disassembly in mitotic cells can be rescued by inhibiting the canonical Aurora A pathway, or perturbating actin dynamics by cytochalasin D The latter compound prevents Fbxo41-dependent cilia shortening in neurons. We propose a mechanism where neurons can shorten their cilia by regulating centriolar levels of Fbxo[41], which affects ciliary signaling capacity
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