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.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Justin
J
Liu
Departments of Molecular and Cellular Biology, and Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Florian T
FT
Merkle
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Avni V
AV
Gandhi
Departments of Molecular and Cellular Biology, and Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
James A
JA
Gagnon
Departments of Molecular and Cellular Biology, and Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Ian G
IG
Woods
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Cindy N
CN
Chiu
Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
Tomomi
T
Shimogori
Departments of Molecular and Cellular Biology, and Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA Division of Sleep Medicine, Harvard University, Cambridge, MA 02115, USA.
Alexander F
AF
Schier
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA dprober@caltech.edu.
David A
DA
Prober
D000818:Animals; D030801:Animals, Genetically Modified; D002469:Cell Separation / Q000379:methods*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D007031:Hypothalamus / Q000196:embryology* / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C571345:Lhx9 protein, zebrafish; D009479:Neuropeptides; D000068797:Orexins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
Hypocretin; Lhx9; Zebrafish