title: Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons.
abstract: Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling.
authors: Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors: Andrew I
authors: AI
authors: Koemeter-Cox
authors: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors: Thomas W
authors: TW
authors: Sherwood
authors: Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors: Jill A
authors: JA
authors: Green
authors: Department of Physiology and Biophysics and Obstetrics and Gynecology, University of Washington, Seattle, WA 98195;
authors: Robert A
authors: RA
authors: Steiner
authors: Department of Cell, Development, and Integrative Biology, University of Alabama at Birmingham Medical School, Birmingham, AL 35294; and.
authors: Nicolas F
authors: NF
authors: Berbari
authors: Department of Cell, Development, and Integrative Biology, University of Alabama at Birmingham Medical School, Birmingham, AL 35294; and.
authors: Bradley K
authors: BK
authors: Yoder
authors: Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093.
authors: Alexander S
authors: AS
authors: Kauffman
authors: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors: Paula C
authors: PC
authors: Monsma
authors: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors: Anthony
authors: A
authors: Brown
authors: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210; mykytyn.1@osu.edu askwith.1@osu.edu.
authors: Candice C
authors: CC
authors: Askwith
authors: Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210; mykytyn.1@osu.edu askwith.1@osu.edu.
authors: Kirk
authors: K
authors: Mykytyn
mesh_terms: D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D012098:Reproduction / Q000502:physiology*; D012741:Sexual Maturation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone
keywords: GPR54; electrophysiology; neuronal primary cilia