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Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans...

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Autores principales: Seifinejad, Ali, Li, Sha, Mikhail, Cyril, Vassalli, Anne, Pradervand, Sylvain, Arribat, Yoan, Pezeshgi Modarres, Hassan, Allen, Bridget, John, Rosalind M., Amati, Francesca, Tafti, Mehdi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708384/
https://www.ncbi.nlm.nih.gov/pubmed/31375626
http://dx.doi.org/10.1073/pnas.1902148116
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author Seifinejad, Ali
Li, Sha
Mikhail, Cyril
Vassalli, Anne
Pradervand, Sylvain
Arribat, Yoan
Pezeshgi Modarres, Hassan
Allen, Bridget
John, Rosalind M.
Amati, Francesca
Tafti, Mehdi
author_facet Seifinejad, Ali
Li, Sha
Mikhail, Cyril
Vassalli, Anne
Pradervand, Sylvain
Arribat, Yoan
Pezeshgi Modarres, Hassan
Allen, Bridget
John, Rosalind M.
Amati, Francesca
Tafti, Mehdi
author_sort Seifinejad, Ali
collection PubMed
description Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT (Peg3, Ahr1, Six6, Nr2f2, and Prrx1) and MCH (Lmx1, Gbx2, and Peg3) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease.
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spelling pubmed-67083842019-09-06 Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons Seifinejad, Ali Li, Sha Mikhail, Cyril Vassalli, Anne Pradervand, Sylvain Arribat, Yoan Pezeshgi Modarres, Hassan Allen, Bridget John, Rosalind M. Amati, Francesca Tafti, Mehdi Proc Natl Acad Sci U S A PNAS Plus Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT (Peg3, Ahr1, Six6, Nr2f2, and Prrx1) and MCH (Lmx1, Gbx2, and Peg3) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease. National Academy of Sciences 2019-08-20 2019-08-02 /pmc/articles/PMC6708384/ /pubmed/31375626 http://dx.doi.org/10.1073/pnas.1902148116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Seifinejad, Ali
Li, Sha
Mikhail, Cyril
Vassalli, Anne
Pradervand, Sylvain
Arribat, Yoan
Pezeshgi Modarres, Hassan
Allen, Bridget
John, Rosalind M.
Amati, Francesca
Tafti, Mehdi
Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title_full Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title_fullStr Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title_full_unstemmed Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title_short Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
title_sort molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708384/
https://www.ncbi.nlm.nih.gov/pubmed/31375626
http://dx.doi.org/10.1073/pnas.1902148116
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