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

Seifinejad A; Li S; Mikhail C; Vassalli A; Pradervand S; Arribat Y; Pezeshgi Modarres H; Allen B; John RM; Amati F; Tafti M

doi:10.1073/pnas.1902148116

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Journal article

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

Seifinejad A Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland; Ali.Seifinejad@unil.ch Mehdi.Tafti@unil.ch.
Li S Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
Mikhail C Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
Vassalli A Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
Pradervand S Genomic Technologies Facility, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
Arribat Y Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
Pezeshgi Modarres H Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Allen B Biomedicine Division, Cardiff School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
John RM Biomedicine Division, Cardiff School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
Amati F Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
Tafti M Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland; Ali.Seifinejad@unil.ch Mehdi.Tafti@unil.ch.

2019-08-04

Published in:

Proceedings of the National Academy of Sciences of the United States of America. - 2019

Induced Pluripotent Stem Cells

Intercellular Signaling Peptides and Proteins

English 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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