Mc3r

Melanocortin receptor 3 (MC3-R)

Spatial tier: RESTRICTED · Class: GPCR · Top region: ARH (Arcuate hypothalamic nucleus) · Positive regions: 28/554

45.5Discovery Score

38.8Targetability Score

CEvidence grade C

What this means: Mc3r: fine CCF profile is restricted toward ARH (top regions: ARH, PVT, LSc, VMH, IF; 28 positive regions); direct spatial validation is still required.

Function in ARH: evidence, prediction, innovation

Gene function

MC3R is one of the five melanocortin receptors, a Gs-coupled class A GPCR activated by alpha-MSH and other POMC-derived peptides and antagonised by AgRP. Unlike MC4R, which drives satiety in downstream nuclei, MC3R acts largely as a presynaptic and somatodendritic autoreceptor within the melanocortin system itself, setting the gain of the circuit rather than directly suppressing feeding.

Region function

The arcuate hypothalamic nucleus sits against the median eminence and contains orexigenic AgRP/NPY and anorexigenic POMC neurons plus GHRH and kisspeptin cells; it is the brain's primary interface for leptin, ghrelin and insulin signals controlling feeding, growth and reproduction.

Published in this region

direct Direct. Gui et al. 2023 showed that MC3R knockout mice have markedly fewer Fos-positive AgRP neurons after a 24 h fast and blunted fasting-induced upregulation of AgRP and NPY mRNA, and that AgRP-neuron-specific MC3R deletion reproduces the blunted response to fasting and ghrelin, establishing a cell-autonomous role in arcuate AgRP cells. Girardet et al. 2018 showed MC3R on AgRP neurons inhibits feeding in female mice, and Lam et al. 2021 linked human MC3R loss-of-function to later puberty and reduced linear growth.

Predicted function

Prediction: because MC3R is the sensor allowing AgRP neurons to be recruited by energy deficit, it should also gate the reproductive and growth arms of the arcuate. Arcuate-restricted MC3R deletion is predicted to leave ad libitum feeding and food-cue-driven AgRP inhibition intact while flattening AgRP recruitment by fasting, cold and ghrelin, delaying pubertal onset and lowering IGF1; an MC3R-selective agonist in the arcuate should suppress AgRP recruitment and blunt refeeding hyperphagia.

Innovation

★★☆☆☆ 2/5 MC3R in arcuate AgRP neurons is now well characterised, though its role in arcuate kisspeptin and GHRH cells linking nutrition to puberty remains comparatively open.

Tools

Mc3r floxed and Mc3r-null mice, Mc3r-Cre and Mc3r-eGFP lines; agonist D-Trp8-gamma-MSH and MC3R-selective analogues; antagonists SHU9119 (non-selective) and MC3R-selective peptides; Agrp-Cre and Pomc-Cre for conditional deletion.

References

Direct evidence located at the region

Mc3r Allen ISH at the CCF centroid of ARH

Allen ISH experiment 74511790, section image 74391595 (section 256): the section that contains the CCF centroid of Arcuate hypothalamic nucleus according to the Allen image-to-atlas alignment (reference_to_image), with a 2 mm window around that point. Left: whole section, red box = window. Middle: ISH signal. Right: Allen's expression-mask view of the same window. open this image in the Allen viewer

Look it up yourself: Allen Mouse Brain ISH for Mc3r Allen reference atlas: ARH (structure 223)ABC Atlas MERFISH viewer(in the ABC Atlas choose dataset MERFISH-C57BL6J-638850-CCF, colour cells by gene "Mc3r" or by parcellation_substructure "ARH")All genes confined to ARH + 3-D brain

Direct spatial evidence

ARH MERFISH region locator — Real single-cell MERFISH coordinates for the ARH (Arcuate hypothalamic nucleus) section -- our own ground-truth data, showing exactly where this region sits, independent of whether the Allen ISH section below is easy to read.

Regional expression figure

Predicted WMB × fine-CCF profile; not direct full-transcriptome spatial measurement.

Spatial profile

ARH

0.946

PVT

0.853

LSc

0.809

VMH

0.707

0.629

0.521

IPDM

0.5

0.483

0.482

0.456

0.446

IMD

0.418

VMPO

0.388

MPN

0.387

PMv

0.352

CLI

0.341

0.315

0.29

LSr

0.283

Evidence and specificity

Evidence status: PREDICTED_FINE
Direct sources: None; predicted localization only
Exclusive threshold: 12 positive regions out of 554
Spatial specificity: 0.324
Top-region fraction: 0.053
Filter status: PASS

Interpretation limits

Cell-type-to-region projection is imputed expression, not direct spatial measurement.
Adult reference atlases do not establish stability across age, sex, strain, state, or disease.
Transcript abundance does not guarantee protein abundance or genetic-tool performance.