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Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009. Epub 2019 Jan 17.

Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.

Author information

1
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
2
The Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
3
The Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
4
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; Pathogenesis of Vascular Infections Unit, INSERM, Institut Pasteur, Paris, France.
5
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; School of Biological and Marine Sciences, University of Plymouth, Plymouth, UK.
6
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
7
Wellcome Sanger Institute, Cambridge, UK; Department of Mathematical and Statistical Sciences, University of Colorado-Denver, Denver, CO 80204, USA.
8
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
9
The Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, TN 37232-0615, USA.
10
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; Wellcome Sanger Institute, Cambridge, UK.
11
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
12
The Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; INSERM U1172, Jean-Pierre Aubert Research Center, Lille, France. Electronic address: sbouret@chla.usc.edu.
13
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: isf20@cam.ac.uk.

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.

KEYWORDS:

AgRP; Neuropilins; Plexins; Pomc; Semaphorin 3s; hypothalamus; obesity

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