Poster abstracts

Poster number 74 submitted by Toni Stubbs

Neuronal cilia modulate D1 mediated dopaminergic signaling

Toneisha Stubbs (Neuroscience Graduate Program ), Kirk Mykytyn (Department of Pharmacology ), Candice Askwith (Department of Neuroscience)

Abstract:
Primary cilia are rod shaped cellular appendages found on nearly every cell type including most central neurons. Dysfunction in the primary cilium is implicated in a class of human disorders termed ciliopathies. Ciliopathies are associated with numerous neuropathologies, including cognitive deficits, obesity, and behavioral phenotypes. Important insight into the function of neuronal cilia in the mammalian brain came from the finding that neuronal cilia are enriched for certain G protein-coupled receptors (GPCRs) and downstream effectors of GPCR signaling, suggesting that neuronal cilia respond to neuromodulators in the extracellular environment. We have previously shown that GPCR ciliary localization is disrupted in neurons from mouse models of the human ciliopathy Bardet-Biedl syndrome (BBS). Interestingly, we found that while certain GPCRs failed to localize to neuronal cilia in BBS mouse models the GPCR dopamine receptor 1 (D1) accumulated in neuronal cilia. These findings led to us to hypothesize that ciliary GPCR mislocalization impacts receptor signaling and contributes to BBS phenotypes such as obesity. Our work shows that disrupting the ciliary localization of D1 by either loss of a BBS protein or lack of cilia, on D1 expressing neurons leads to decreased D1 mediated dopaminergic signaling. Additionally, we observed that ciliary mislocalization of D1 also resulted in obesity. Further investigation showed that this increase in weight was not due to increased food intake but was associated with decreased locomotor activity. Taken all together these observations show that proper cilia formation and function are required for normal dopaminergic signaling in D1 expressing neurons. To further explore the impact that neuronal cilia have on D1 expressing neurons future directions and ongoing work aims to 1) identify the proteins involved in trafficking D1 to the restricted ciliary membrane and 2) identify the downstream transcriptional consequences of D1 ciliary mislocalization on D1 expressing neurons.

References:
1. Domire, J. S., Green, J. A., Lee, K. G., Johnson, A. D., Askwith, C. C., & Mykytyn, K. (2010). Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the bardet-biedl syndrome proteins. Cellular and Molecular Life Sciences : CMLS, 68(17), 2951-2960. doi:10.1007/s00018-010-0603-4
2. Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C., & Mykytyn, K. (2008). Bardet Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proceedings of the National Academy of Sciences - PNAS, 105(11), 4242-4246. doi:10.1073/pnas.0711027105
3. Hilgendorf, K. I., Johnson, C. T., & Jackson, P. K. (2016). The primary cilium as a cellular receiver: Organizing ciliary GPCR signaling. Current Opinion in Cell Biology, 39, 84-92. doi:10.1016/j.ceb.2016.02.008

Keywords: Dopamine Receptor 1, Neuronal Primary Cilia, Bardet Biedl Syndrome