Abstract
The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.
Highlights
Immunohistochemical analyses in brains of rats showed that ADCY3/MCHR1 double-positive neuronal primary cilia were localized in discrete regions, including CPu and cerebral cortex (Diniz et al, 2020a)
We established the causal effects of Melanin-concentrating hormone (MCH) signaling pathways on cilia length
We demonstrated that the stimulation of the MCH system through direct agonist activation of the MCHR1 or via optogenetic and chemogenic excitation of MCH neurons causes a significant decrease in cilia length
Summary
Melanin-concentrating hormone (MCH), a 19 amino acid hypothalamic neuropeptide, is involved in numerous functions, including food intake, energy homeostasis, arousal, sleep, learning and memory, cognition, emotions, and maternal behavior (Arletti et al, 1992; Blouin et al, 2013; Borowsky et al, 2002; Chaki et al, 2005; Cohen et al, 2014; Della-Zuana et al, 2002; Gonzalez et al, 1997; Gonzalez et al, 1996; Onaka et al, 2012; Pedersen et al, 1994; Pedersen and Prange, 1979; Vawter et al, 2019). MCHR1 localization on cilia membranes might be the basis of the uniqueness of these receptors in regulating ciliary signaling In support of this notion, in vitro studies demonstrated that MCH treatment shortened the length of cilia in human retinal pigmented epithelial (hRPE1) cells transfected with MCHR1. A recent study by the Saito group demonstrated that treatment of hippocampus slice cultures with MCH induced cilia shortening in the CA1 region (Kobayashi et al, 2021) Their results revealed a marked increase in MCH mRNA expression in the lateral hypothalamus of fasting mice which correlated with a reduction of MCHR1-positive cilia lengths in the hippocampal CA1 region (Kobayashi et al, 2021). We used multiple techniques to manipulate the MCH system, including pharmacological, genetic, optogenetic and chemogenetic approaches to determine how alterations in the MCH system affect cilia length
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
