Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9
Copyright policy )Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9
Loss of neurons that express the neuropeptide hypocretin (Hcrt) has been implicated in narcolepsy, a debilitating disorder characterized by excessive daytime sleepiness and cataplexy. Cell replacement therapy, using Hcrt-expressing neurons generated in vitro, is a potentially useful therapeutic approach, but factors sufficient to specify Hcrt neurons are unknown. Using zebrafish as a high-throughput system to screen for factors that can specify Hcrt neurons in vivo, we identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient to specify Hcrt neurons. We found that Lhx9 can directly induce hcrt expression and we identified two potential Lhx9 binding sites in the zebrafish hcrt promoter. Akin to its function in zebrafish, we found that Lhx9 is sufficient to specify Hcrt-expressing neurons in the developing mouse hypothalamus. Our results elucidate an evolutionarily conserved role for Lhx9 in Hcrt neuron specification that improves our understanding of Hcrt neuron development.
- University of Basel Switzerland
- Harvard University United States
- Harvard Stem Cell Institute, Cambridge, MA, USA United States
- University of Cambridge United Kingdom
- California Institute of Technology United States
Hypocretin, Green Fluorescent Proteins, Hypothalamus, 610, Electrophoretic Mobility Shift Assay, Cell Separation, Lhx9, Animals, Genetically Modified, Mice, Animals, Cloning, Molecular, Biology, Zebrafish, DNA Primers, Neurons, Orexins, Reverse Transcriptase Polymerase Chain Reaction, Neuropeptides, Intracellular Signaling Peptides and Proteins, Genetics and Genomics, Zebrafish Proteins, Microarray Analysis, Immunohistochemistry, High-Throughput Screening Assays, Gene Expression Regulation, Animal Sciences, Gene Knockdown Techniques, Transcription Factors
Hypocretin, Green Fluorescent Proteins, Hypothalamus, 610, Electrophoretic Mobility Shift Assay, Cell Separation, Lhx9, Animals, Genetically Modified, Mice, Animals, Cloning, Molecular, Biology, Zebrafish, DNA Primers, Neurons, Orexins, Reverse Transcriptase Polymerase Chain Reaction, Neuropeptides, Intracellular Signaling Peptides and Proteins, Genetics and Genomics, Zebrafish Proteins, Microarray Analysis, Immunohistochemistry, High-Throughput Screening Assays, Gene Expression Regulation, Animal Sciences, Gene Knockdown Techniques, Transcription Factors
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