Biology subjects

Doi, S.

Publications and source records attributed to Doi, S..

3 recordsLinked to original sources

bioRxiv2026

GPR182 promotes atherosclerosis via facilitating arterial lipid deposition

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerosis; however, the molecular mechanisms underlying lipid plaque formation within the artery wall remain poorly understood. Here, we identify GPR182, a recently characterized lipoprotein receptor of the atypical chemokine receptor family, as a key mediator of lipid deposition in the aortic endothelium during atherosclerosis. Genetic depletion of GPR182 protects against atherosclerosis across multiple mouse models without altering circulating cholesterol levels or immune cell recruitment to plaques. GPR182 is expressed by aortic endothelial cells (ECs) and is further upregulated during disease progression. GPR182 mediates LDL uptake by aortic ECs both in vitro and in vivo. Blockade of GPR182 with a monoclonal antibody reduces lipid uptake in the aorta and attenuates disease progression under hypercholesterolemic conditions. Collectively, these findings identify endothelial GPR182 as a critical regulator of aortic lipid deposition and atherosclerotic plaque formation and support GPR182 inhibition as a promising therapy for atherosclerotic cardiovascular disease.

molecular biology↗

bioRxiv2026

Visualization of neuronal morphology of the suprachiasmatic nucleus vasopressin neurons by Cre/FLPe-based genetic two-step sparse labelling - GT-SPARCL

Resolving the morphology of individual neurons in densely packed brain regions remains challenging. Sparse labeling is essential for delineating cellular architecture, yet achieving reproducible low-density labeling e.g. < 1% has been a persistent technical hurdle/problem. We present a genetically encoded two-step strategy, GT-SPARCL (Genetic Two-Step Sparse Cre/FLPe Combination Labeling), which leverages two independent stochastic recombination events to deliver stable, tunable low-density labeling in mice. As a proof of concept, we applied this method to visualizing arginine vasopressin (AVP) neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker composed of [~]10,000 neurons per side in mice. Using two-photon imaging of whole-mount SCN blocks, we reconstructed individual AVP neurons and uncovered previously under-resolved morphological heterogeneity. Based on axonal trajectories, we distinguished five structural types, including subclasses with commissural projections to the contralateral SCN and others extending projections beyond the nucleus. The majority ([~]70%) exhibited projections both within and outside the ipsilateral SCN, whereas the second most dominant subset ([~]20%) projected exclusively outside the SCN, representing an output-biased type. In contrast, neurons projecting exclusively within the ipsilateral SCN were exceptionally rare, suggesting that "dedicated" local-circuit AVP neurons do not form a major structural subtype. Collectively, our data indicate that AVP neurons are not structurally uniform but instead comprise diverse projection-defined subtypes, implying subtype-depen-dent contributions to intra-SCN communication, bilateral coupling, and circadian output. Beyond the SCN, our GT-SPARCL method may be applicable for achieving low-density labelling of neurons that can be defined by other specific Cre mouse lines.

neuroscience↗

bioRxiv2021

Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock

Background and PurposeGpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with no established physiological function in vivo. The purpose of this study was to determine the role of Gpr19 in the circadian clock system. Experimental ApproachWe examined whether and how the master circadian clock neurons in the suprachiasmatic nucleus (SCN) express Gpr19. By analysing Gpr19-deficient (Gpr19-/-) mice, we asked whether Gpr19 has a role in modulating free-running period and light resetting capacity of the circadian clock. Key ResultsCompared with the known common core clock genes, Gpr19 was identified to show several distinct yet limited features related to the circadian clock. Gpr19 mRNA was mainly expressed in the middle-to-dorsal region of the SCN. A conserved cAMP-responsive element within the Gpr19 promoter drove the circadian expression of Gpr19. Gpr19-/- mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity in a 12-h light/12-h dark cycle. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. Gpr19-/- mice had a reduced capacity for phase shift to early subjective night light. The defect was only observed for phase-delay, but not phase-advance, and accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral part of the SCN, in Gpr19-/- mice. Conclusion and ImplicationsGpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and thus may be a potential target for alleviating circadian clock disorders. O_LIWhat is already known: Gpr19 is an evolutionarily conserved class-A orphan receptor with no established physiological role in vivo. The SCN is a light-entrainable master circadian pacemaker governing daily rhythms of behaviour and physiology. C_LIO_LIWhat this study adds: Gpr19 is an SCN-enriched orphan GPCR whose levels fluctuate in a circadian fashion. Gpr19 is a functional clock modulator involved in period determination and phase resetting. C_LIO_LIClinical significance: Targeting the orphan receptor Gpr19 may provide a therapeutic approach for alleviating circadian clock disorders. C_LI

neuroscience↗