Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Agatha A Van Der Klaauw,Richard B Simerly,Rebecca Bounds,Stephen O’Rahilly,Elena G Bochukova,James E.N Minchin,Panna Tandon,Soyoung Park,Elana Henning,Sofia Papadia,Sophie Croizier,I Sadaf Farooqi,Inês Barroso,Audrey E Hendricks,Edson Mendes De Oliveira,Susanna E Riley,Vanisha Mistry,Matthew C Banton,Julia M Keogh,E Y Jones ,Y Kong ,Sébastien G Bouret ,Lukas Kurt Josef Stadler

doi:10.1016/j.cell.2018.12.009

Abstract

SummaryHypothalamic 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.

Highlights

Using hypothalamic explants from mice, we demonstrated that Sema3 signaling via Nrp2 receptors drives the development of Pomc projections from the arcuate nucleus of the hypothalamus (ARH) to the paraventricular nucleus of the hypothalamus (PVH)
Deletion of Nrp2 in Pomc neurons, reduced the density of Pomc projections and caused weight gain in young mice. These findings demonstrate the role of Sema3 signaling in the development of melanocortin circuits that modulate energy homeostasis, findings that have relevance to the understanding of disorders of human hypothalamic development
To test whether there was an enrichment for very rare predicted functional variants in 13 genes involved in Semaphorin 3 signaling in severely obese cases compared to controls, we compared exome sequencing data from the final UK10K data release of 982 severely obese individuals with that of 4,449 healthy controls recruited to the INTERVAL study (Moore et al, 2014)

Summary

Methods

Studies in Humans Sequencing, variant calling, and quality control Details about sequencing and variant calling for the severe childhood onset obesity project (SCOOP, UK individuals of European ancestry recruited to the GOOS cohort) cases (Hendricks et al, 2017), as part of the UK10K exomes, and the INTERVAL controls have been reported previously (Singh et al, 2016). Using PLINK/SEQ (Purcell et al, 2007) we calculated individual gene region burden test-statistics for an enrichment in cases compared to controls of very rare (MAF < 0.025%) variants meeting one of two predicted functional requirements: functional or loss of function, or only loss of function. We used the SMP utility to calculate the gene set enrichment while controlling for exome-wide differences

Results

Discussion

Conclusion