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

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_16F0A8FF99CE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Seifinejad A., Li S., Mikhail C., Vassalli A., Pradervand S., Arribat Y., Pezeshgi Modarres H., Allen B., John R.M., Amati F., Tafti M.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
20/08/2019
Peer-reviewed
Oui
Volume
116
Number
34
Pages
17061-17070
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Animals, Hypothalamic Hormones/genetics, Hypothalamic Hormones/metabolism, Hypothalamus/cytology, Hypothalamus/metabolism, Induced Pluripotent Stem Cells/cytology, Induced Pluripotent Stem Cells/metabolism, Intercellular Signaling Peptides and Proteins/genetics, Intercellular Signaling Peptides and Proteins/metabolism, Melanins/genetics, Melanins/metabolism, Mice, Mice, Transgenic, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neurons/cytology, Neurons/metabolism, Orexins/genetics, Orexins/metabolism, Pituitary Hormones/genetics, Pituitary Hormones/metabolism, HCRT/OREXIN, MCH, Peg3, iPSC, transcription factor
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation / Projects / 320030_170062
Create date
09/08/2019 14:01
Last modification date
04/04/2020 6:17
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