Human semaphorin 3 variants link melanocortin circuit development and energy balance

Agatha A. Van Der Klaauw; Sophie Croizier; Edson Mendes De Oliveira; Lukas K.j. Stadler; Soyoung Park; Youxin Kong; Matthew C. Banton; Panna Tandon; Audrey E. Hendricks; Julia M. Keogh; Susanna E. Riley; Sofia Papadia; Elana Henning; Rebecca Bounds; Elena G. Bochukova; Vanisha Mistry; Stephen O’rahilly; Richard B. Simerly; INTERVAL; UK10K Consortium; James E.N. Minchin; Inês Barroso; E. Yvonne Jones; Sebastien G. Bouret; I. Sadaf Farooqi

doi:10.1016/j.cell.2018.12.009

Human semaphorin 3 variants link melanocortin circuit development and energy balance

Agatha A. Van Der Klaauw, Sophie Croizier, Edson Mendes De Oliveira, Lukas K.j. Stadler, Soyoung Park, Youxin Kong, Matthew C. Banton, Panna Tandon, Audrey E. Hendricks, Julia M. Keogh, Susanna E. Riley, Sofia Papadia, Elana Henning, Rebecca Bounds, Elena G. Bochukova, Vanisha Mistry, Stephen O’rahilly, Richard B. Simerly, INTERVAL, UK10K ConsortiumJames E.N. Minchin, Inês Barroso, E. Yvonne Jones, Sebastien G. Bouret, I. Sadaf Farooqi

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	729-742
Number of pages	22
Journal	Cell
Volume	176
Issue number	4
Early online date	17 Jan 2019
DOIs	https://doi.org/10.1016/j.cell.2018.12.009
Publication status	Published - 7 Feb 2019

Keywords / Materials (for Non-textual outputs)

AgRP
obesity
Semaphorin 3s
Neuropilins
Plexins
hypothalamus
Pomc

Access to Document

10.1016/j.cell.2018.12.009Licence: Creative Commons: Attribution (CC-BY)

Human Semaphorin 3 Variants Link MelanocortinFinal published version, 11.1 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.cell.com/cell/fulltext/S0092-8674(18)31623-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418316234%3Fshowall%3Dtrue

BHF Research Excellence Award (2) (renewal) Grant 1
Mullins, J., Bailey, M., Beqqali, A., Caporali, A., Crisan, M., Mansley, M., Meloni, M., Reynolds, R. & Wu, J.
UK-based charities
1/04/14 → 30/06/19
Project: Research

James Minchin
- james.minchined.acuk
- Deanery of Clinical Sciences - Senior Lecturer
- Centre for Cardiovascular Science
Person: Academic: Research Active

Cite this

Van Der Klaauw, A. A., Croizier, S., Mendes De Oliveira, E., Stadler, L. K. J., Park, S., Kong, Y., Banton, M. C., Tandon, P., Hendricks, A. E., Keogh, J. M., Riley, S. E., Papadia, S., Henning, E., Bounds, R., Bochukova, E. G., Mistry, V., O’rahilly, S., Simerly, R. B., INTERVAL, ... Farooqi, I. S. (2019). Human semaphorin 3 variants link melanocortin circuit development and energy balance. Cell, 176(4), 729-742. https://doi.org/10.1016/j.cell.2018.12.009

@article{064d68557af5483b933736b99faa0c9a,

title = "Human semaphorin 3 variants link melanocortin circuit development and energy balance",

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, obesity, Semaphorin 3s, Neuropilins, Plexins, hypothalamus, Pomc",

author = "{Van Der Klaauw}, {Agatha A.} and Sophie Croizier and {Mendes De Oliveira}, Edson and Stadler, {Lukas K.j.} and Soyoung Park and Youxin Kong and Banton, {Matthew C.} and Panna Tandon and Hendricks, {Audrey E.} and Keogh, {Julia M.} and Riley, {Susanna E.} and Sofia Papadia and Elana Henning and Rebecca Bounds and Bochukova, {Elena G.} and Vanisha Mistry and Stephen O{\textquoteright}rahilly and Simerly, {Richard B.} and INTERVAL and {UK10K Consortium} and Minchin, {James E.N.} and In{\^e}s Barroso and Jones, {E. Yvonne} and Bouret, {Sebastien G.} and Farooqi, {I. Sadaf}",

year = "2019",

month = feb,

day = "7",

doi = "10.1016/j.cell.2018.12.009",

language = "English",

volume = "176",

pages = "729--742",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

}

Van Der Klaauw, AA, Croizier, S, Mendes De Oliveira, E, Stadler, LKJ, Park, S, Kong, Y, Banton, MC, Tandon, P, Hendricks, AE, Keogh, JM, Riley, SE, Papadia, S, Henning, E, Bounds, R, Bochukova, EG, Mistry, V, O’rahilly, S, Simerly, RB, INTERVAL, UK10K Consortium, Minchin, JEN, Barroso, I, Jones, EY, Bouret, SG & Farooqi, IS 2019, 'Human semaphorin 3 variants link melanocortin circuit development and energy balance', Cell, vol. 176, no. 4, pp. 729-742. https://doi.org/10.1016/j.cell.2018.12.009

TY - JOUR

T1 - Human semaphorin 3 variants link melanocortin circuit development and energy balance

AU - Van Der Klaauw, Agatha A.

AU - Croizier, Sophie

AU - Mendes De Oliveira, Edson

AU - Stadler, Lukas K.j.

AU - Park, Soyoung

AU - Kong, Youxin

AU - Banton, Matthew C.

AU - Tandon, Panna

AU - Hendricks, Audrey E.

AU - Keogh, Julia M.

AU - Riley, Susanna E.

AU - Papadia, Sofia

AU - Henning, Elana

AU - Bounds, Rebecca

AU - Bochukova, Elena G.

AU - Mistry, Vanisha

AU - O’rahilly, Stephen

AU - Simerly, Richard B.

AU - INTERVAL

AU - UK10K Consortium

AU - Minchin, James E.N.

AU - Barroso, Inês

AU - Jones, E. Yvonne

AU - Bouret, Sebastien G.

AU - Farooqi, I. Sadaf

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

KW - AgRP

KW - obesity

KW - Semaphorin 3s

KW - Neuropilins

KW - Plexins

KW - hypothalamus

KW - Pomc

U2 - 10.1016/j.cell.2018.12.009

DO - 10.1016/j.cell.2018.12.009

M3 - Article

SN - 0092-8674

VL - 176

SP - 729

EP - 742

JO - Cell

JF - Cell

IS - 4

ER -

Human semaphorin 3 variants link melanocortin circuit development and energy balance

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

BHF Research Excellence Award (2) (renewal) Grant 1

Profiles

James Minchin

Cite this