Yi-Chun Hsiao, Jesús Muñoz-Estrada, Karina Tuz and Russell J. Ferland
Journal of Neuroscience 19 March 2021, JN-RM-2993-20; DOI: https://doi.org/10.1523/JNEUROSCI.2993-20.2021
Abstract
The Abelson-helper integration site 1 (AHI1) gene encodes for a ciliary transition zone localizing protein that when mutated causes the human ciliopathy, Joubert syndrome. We prepared and examined neuronal cultures derived from male and female embryonic Ahi1 +/+ and Ahi1 -/- mice (littermates) and found that the distribution of ciliary MchR1 was significantly reduced in Ahi1 -/- neurons; however, the total and surface expression of MchR1 on Ahi1 -/- neurons was similar to controls (Ahi1 +/+). This indicates that a pathway for MchR1 trafficking to the surface plasma membrane is intact, but the process of targeting MchR1 into cilia is impaired in Ahi1 deficient mouse neurons, indicating a role for Ahi1 in localizing MchR1 to the cilium. Mouse Ahi1 -/- neurons that fail to accumulate MchR1 in the ciliary membrane have significant decreases in two downstream MchR1 signaling pathways (cAMP and Erk) upon MCH stimulation. These results suggest that the ciliary localization of MchR1 is necessary and critical for MchR1 signaling, with Ahi1 participating in regulating MchR1 localization to cilia, and further supporting cilia as critical signaling centers in neurons.