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Article Dans Une Revue Cell Année : 2019

Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Soyoung Park

Résumé

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.
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hal-02375383 , version 1 (21-10-2021)

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Agatha van Der Klaauw, Sophie Croizier, Edson Mendes de Oliveira, Lukas K.J. Stadler, Soyoung Park, et al.. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell, 2019, 176 (4), pp.729-742.e18. ⟨10.1016/j.cell.2018.12.009⟩. ⟨hal-02375383⟩
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