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Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

van der Klaauw, Agatha A., Croizier, Sophie, Mendes de Oliveira, Edson, Stadler, Lukas K.J., Park, Soyoung, Kong, Youxin, Banton, Matthew C., Tandon, Panna, Hendricks, Audrey E., Keogh, Julia M., Riley, Susanna E., Papadia, Sofia, Henning, Elana, Bounds, Rebecca, Bochukova, Elena G., Mistry, Vanisha, O’Rahilly, Stephen, Simerly, Richard B., Minchin, James E.N., Barroso, Inês, Jones, E. Yvonne, Bouret, Sebastien G., Farooqi, I. Sadaf
Cell 2019 v.176 no.4 pp. 729-742.e18
Danio rerio, adiposity, energy expenditure, genes, homeostasis, humans, mice, mutagenesis, neurons, pro-opiomelanocortin, receptors, secretion, weight gain
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.