bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/451344

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov, K.·Uytingco, C.·Green, W.·Zhang, L.·Schurmans, S.·Martens, J. R.
View original source ↗Export metadata ↓

Abstract

Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs. Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation. However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level. These findings implicate phosphoinositide-dependent regulation of active Ca2+ extrusion in OSNs whereby controlling the rate of sensory adaptation.\n\nSignificance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Ukhanov, K., Uytingco, C., Green, W., Zhang, L., Schurmans, S., Martens, J. R.. 2018-10-23. INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome. https://doi.org/10.1101/451344

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Feasible closed-loop stimulation for neural latent dynamics control

Modern neuroscience benefits from powerful computational and experimental methods for studying neural populations, including latent dynamics models that predict behavior with few dimensions. But despite their explanatory utility, latent factors are seldom targeted explicitly with experimental perturbations, leaving causal relationships to behavior and inferred dynamical landscapes untested. A promising solution is closed-loop, multi-channel optogenetic control, which, when paired with model predictions, could steer neural trajectories in real time--a feat impossible for traditional, hand-designed stimulation. However, because closed-loop latent control has not been demonstrated in vivo, the hardware and software requirements remain unclear--particularly the necessary stimulation dimensionality and how limited resources such as implant volume and bandwidth should be allocated between stimulation and recording capabilities. Preliminary experiments would thus help guide ongoing technological development. As large-scale exploration of these design spaces in vivo is prohibitively expensive, we conducted a high-throughput simulation survey using biophysically grounded spiking neural networks. We found that low-dimensional actuation is sufficient: in the reference configuration, ~20% of the stimulation channels achieved ~85% of peak control performance, far fewer than the number of neurons. Furthermore, allocating channels roughly equally between stimulation and recording optimized behavioral control, whereas pairing many electrodes with a single light source--the prevailing practice in experimental labs--performed poorly. Even without heavily optimizing modeling or control, we obtained >60% tracking error reduction and >90% evoked behavior accuracy on average for optimal channel counts. These results held across extensive parameter variations, suggesting that closed-loop latent control is feasible with accessible channel counts and establishing design principles for future tool development and in vivo experiments.

neuroscience↗
bioRxiv2026

Identification of Kinome Biomarkers and Therapeutic Rescue in cGMP-Linked Retinal Degeneration

Inherited retinal degenerations, such as Retinitis Pigmentosa (RP) and Leber's congenital amaurosis (LCA), are major causes of progressive and irreversible vision loss. The large number of genes associated with these disorders makes their clinical and molecular characterization difficult, while systemic biomarkers for disease progression or treatment response remain limited. These challenges were addressed by targeting cGMP-associated mechanisms shared by RP and LCA and integrating systemic biomarker profiling with retinal outcomes. Kinase activity analysis (kinome analysis) in peripheral blood mononuclear cells distinguished healthy and diseased states and captured therapy-associated signatures in rd10 mice treated with LP-CN03, a liposomal formulation of the cGMP analog CN03. This first systemic analysis in a therapeutically responsive animal model highlights kinome analysis as a potential translational readout. Given shared cGMP signaling in RP and AIPL1-associated LCA, LP-CN03's therapeutic potential was further evaluated in a new CRISPR-Cas9-generated Aipl1-/- mouse model. Treatment with LP-CN03 preserved retinal structure and function, as shown by electroretinography, longitudinal optical coherence tomography, fundus imaging, optomotor testing, and photoreceptor-specific gene expression. Together, these findings provide independent in vivo evidence for the neuroprotective effect of LP-CN03 in both cGMP-related RP and LCA, also highlighting the translational value of kinome profiling.

neuroscience↗
bioRxiv2026

Shikonin alleviates bone cancer pain through suppression of spinal IGF2-associated p38 MAPK signaling

Background Bone cancer pain (BCP) is a debilitating complication of advanced cancer that substantially impairs physical function and emotional wellbeing. Current pharmacological treatments often provide incomplete analgesia and may be limited by adverse effects. Shikonin, a bioactive naphthoquinone derived from Lithospermum erythrorhizon, exhibits analgesic and anti inflammatory activities, but its effects and underlying mechanisms in BCP remain unclear. Methods A rat model of BCP was established by intratibial inoculation of luciferase labeled MADB106 cells. The analgesic and behavioral effects of intrathecal Shikonin were evaluated using mechanical and thermal nociceptive assays, CatWalk gait analysis, the open field test (OFT), elevated plus maze (EPM), light/dark box (LDB) test, and rotarod testing. Bioluminescence imaging and hematoxylin eosin staining were used to characterize tumor development and bone pathology. Spinal dorsal horn transcriptomic sequencing was performed to identify candidate molecular pathways. Western blotting, quantitative PCR, and ELISA were used to examine IGF2 associated p38 MAPK signaling and proinflammatory cytokines. The functional involvement of IGF2 and p38 associated signaling was further evaluated using intrathecal IGF2 siRNA and the p38 inhibitor Adezmapimod (SB203580). Results Intrathecal Shikonin produced dose and time dependent antinociceptive effects in BCP rats, with an estimated ED50 of 29.80 g/kg, and did not produce an apparent impairment of rotarod performance. Shikonin also improved gait abnormalities and pain related anxiety like behaviors. Transcriptomic analysis identified Igf2 as a candidate gene responsive to Shikonin treatment, and spinal IGF2 and p38 phosphorylation were increased during BCP development. Shikonin significantly reduced IGF2 expression and p38 phosphorylation in the spinal dorsal horn, accompanied by decreased IL 6, IL 1{beta};, and TNF ; expression in spinal tissue. IGF2 knockdown reproduced the analgesic and behavioral effects of Shikonin and reduced p38 phosphorylation, whereas p38 inhibition reproduced key behavioral effects without a marked change in IGF2 expression. Combined treatment with Shikonin and either IGF2 knockdown or p38 inhibition produced no significant additional behavioral benefit. Conclusion Intrathecal Shikonin alleviates nociceptive hypersensitivity, functional impairment, and pain related anxiety like behaviors in rats with MADB106 induced BCP. The phenocopying and non additive effects of IGF2 knockdown and p38 inhibition support the involvement of an IGF2 associated p38 MAPK signaling axis in the analgesic actions of Shikonin.

neuroscience↗