Abstract
Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. Across eukaryotes, intraflagellar transport (IFT) facilitates cilia biogenesis and cargo trafficking, but our understanding of mammalian IFT is insufficient. Here we perform live analysis of cilia ultrastructure, composition and cargo transport in native mammalian tissue using olfactory sensory neurons. Proximal and distal axonemes of these neurons show no bias towards IFT kinesin-2 choice, and Kif17 homodimer is dispensable for distal segment IFT. We identify Bardet–Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles. Conversely, subpopulations of peripheral membrane proteins, as well as transmembrane olfactory signalling pathway components, are capable of IFT but with significantly less frequency and/or duration. Our results yield a model for IFT and cargo trafficking in native mammalian cilia and may explain the penetrance of specific ciliopathy phenotypes in olfactory neurons.
Highlights
Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems
BBS3:green FP (GFP) Tip general, the genetic loci underlying clinically distinct ciliopathies are coincident with biochemical data showing interactions between their encoded proteins and cooperation as a functional unit[54]
In C. elegans the Bardet–Biedl syndrome proteins (BBSome) is essential for intraflagellar transport (IFT) particle integrity and motor coordination[37,55,56], but in C. reinhardtii Bardet–Biedl syndrome (BBS) proteins are dispensable for IFT and flagellar biogenesis[34]
Summary
Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. IFT has been described in only a small number of studies on cultured cells[13,14,15,16,17,18] and the fundamental questions of how the mammalian IFT machinery operates in native cilia or whether it associates with BBS proteins have not been addressed. These questions are relevant in the context of IFT gene mutations causing BBS7 and BBS disease penetrance within the olfactory system where BBS protein disruption is detrimental to ciliation and odour detection[9,10]. Our findings provide framework for the first model of IFT in a native mammalian setting and implicate the relationship between IFT and the BBSome as a likely culprit in the penetrance of BBS mutations on ciliation in the olfactory epithelium (OE)
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