Abstract
ABSTRACTThe lipid composition of the primary cilia membrane is emerging as a critical regulator of cilia formation, maintenance and function. Here, we show that conditional deletion of the phosphoinositide 5′-phosphatase gene Inpp5e, mutation of which is causative of Joubert syndrome, in terminally developed mouse olfactory sensory neurons (OSNs), leads to a dramatic remodeling of ciliary phospholipids that is accompanied by marked elongation of cilia. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], which is normally restricted to the proximal segment redistributed to the entire length of cilia in Inpp5e knockout mice with a reduction in phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] and elevation of phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] in the dendritic knob. The redistribution of phosphoinositides impaired odor adaptation, resulting in less efficient recovery and altered inactivation kinetics of the odor-evoked electrical response and the odor-induced elevation of cytoplasmic Ca2+. Gene replacement of Inpp5e through adenoviral expression restored the ciliary localization of PI(4,5)P2 and odor response kinetics in OSNs. Our findings support the role of phosphoinositides as a modulator of the odor response and in ciliary biology of native multi-ciliated OSNs.
Highlights
The olfactory system in animals and humans is optimally tuned to recognize a diverse set of chemical cues and odorants in the environment
Distribution of PIP2 in mature olfactory sensory neurons (OSNs) was measured using en face confocal microscopy of intact olfactory epithelium transduced with adenovirus encoding the PLCδ1-PH (PLCPH) domain tagged with GFP (Fig. 1)
In wild-type (WT) littermate control mice, 52.7±10.8% (n=318, 4 mice) of cells infected with the PLCPH probe had an extremely polarized distribution of PIP2 with an accumulation in the OSN knob and no ciliary localization (Fig. 1A,C; Fig. S1B; note, all results presented in the main text are given as mean±s.e.m.)
Summary
The olfactory system in animals and humans is optimally tuned to recognize a diverse set of chemical cues and odorants in the environment. Initial binding of an odorant to an olfactory receptor activates a. When transiently elevated inside cilia, cAMP opens cyclic nucleotide-gated channels (CNGCs) leading to the influx of Ca2+ ions, which, in turn, activates the ADCY3-dependent chloride channels (TMEM16B, known as ANO2) as a secondary amplification cascade (Kaupp and Seifert, 2002; Reisert et al, 2005; Stephan et al, 2009). Despite all the studies that have dissected the main components of this cascade, much less is understood about how the transduction is tuned and regulated within the cilia microenvironment to support optimal sensitivity and resolution of the incoming sensory information
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