dc.contributor.author | van der Klaauw, AA | |
dc.contributor.author | Croizier, S | |
dc.contributor.author | Mendes de Oliveira, E | |
dc.contributor.author | Stadler, LKJ | |
dc.contributor.author | Park, S | |
dc.contributor.author | Kong, Y | |
dc.contributor.author | Banton, MC | |
dc.contributor.author | Tandon, P | |
dc.contributor.author | Hendricks, AE | |
dc.contributor.author | Keogh, JM | |
dc.contributor.author | Riley, SE | |
dc.contributor.author | Papadia, S | |
dc.contributor.author | Henning, E | |
dc.contributor.author | Bounds, R | |
dc.contributor.author | Bochukova, EG | |
dc.contributor.author | Mistry, V | |
dc.contributor.author | O'Rahilly, S | |
dc.contributor.author | Simerly, RB | |
dc.contributor.author | INTERVAL | |
dc.contributor.author | UK10K Consortium | |
dc.contributor.author | Minchin, JEN | |
dc.contributor.author | Barroso, I | |
dc.contributor.author | Jones, EY | |
dc.contributor.author | Bouret, SG | |
dc.contributor.author | Farooqi, IS | |
dc.date.accessioned | 2019-05-10T10:33:14Z | |
dc.date.available | 2018-12-05 | |
dc.date.available | 2019-05-10T10:33:14Z | |
dc.date.issued | 2019-01-17 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/57397 | |
dc.description.abstract | 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. | en_US |
dc.language | eng | |
dc.language.iso | en | en_US |
dc.publisher | Elsevier Inc. | en_US |
dc.relation.ispartof | Cell | |
dc.rights | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | AgRP | en_US |
dc.subject | Neuropilins | en_US |
dc.subject | Plexins | en_US |
dc.subject | Pomc | en_US |
dc.subject | Semaphorin 3s | en_US |
dc.subject | hypothalamus | en_US |
dc.subject | obesity | en_US |
dc.title | Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. | en_US |
dc.type | Article | en_US |
dc.rights.holder | © 2018 The Authors. Published by Elsevier Inc. | |
dc.identifier.doi | 10.1016/j.cell.2018.12.009 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/30661757 | en_US |
pubs.notes | No embargo | en_US |
pubs.publication-status | Published online | en_US |
pubs.publisher-url | https://doi.org/10.1016/j.cell.2018.12.009 | |
dcterms.dateAccepted | 2018-12-05 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |