BBS4 is required for intraflagellar transport coordination and basal body number in mammalian olfactory cilia

J Cell Sci. 2019 Feb 15;132(5):jcs222331. doi: 10.1242/jcs.222331.

Abstract

Bardet-Beidl syndrome (BBS) manifests from genetic mutations encoding for one or more BBS proteins. BBS4 loss impacts olfactory ciliation and odor detection, yet the cellular mechanisms remain unclear. Here, we report that Bbs4-/- mice exhibit shorter and fewer olfactory sensory neuron (OSN) cilia despite retaining odorant receptor localization. Within Bbs4-/- OSN cilia, we observed asynchronous rates of IFT-A/B particle movements, indicating miscoordination in IFT complex trafficking. Within the OSN dendritic knob, the basal bodies are dynamic, with incorporation of ectopically expressed centrin-2 and γ-tubulin occurring after nascent ciliogenesis. Importantly, BBS4 loss results in the reduction of basal body numbers separate from cilia loss. Adenoviral expression of BBS4 restored OSN cilia lengths and was sufficient to re-establish odor detection, but failed to rescue ciliary and basal body numbers. Our results yield a model for the plurality of BBS4 functions in OSNs that includes intraciliary and periciliary roles that can explain the loss of cilia and penetrance of ciliopathy phenotypes in olfactory neurons.

Keywords: Bardet–Biedl syndrome; Basal body; Gene therapy; Intraflagellar transport; Olfactory cilia; Peripheral olfactory system.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bardet-Biedl Syndrome / metabolism*
  • Basal Bodies / pathology
  • Cells, Cultured
  • Cilia / physiology*
  • Disease Models, Animal
  • Flagella / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Olfactory Receptor Neurons / physiology*
  • Phenotype
  • Protein Transport
  • Smell
  • Trimethoprim, Sulfamethoxazole Drug Combination / metabolism
  • Tubulin / metabolism

Substances

  • BBS4 protein, mouse
  • Microtubule-Associated Proteins
  • Tubulin
  • Trimethoprim, Sulfamethoxazole Drug Combination