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Development. 2015 Mar 15;142(6):1113-24. doi: 10.1242/dev.117424. Epub 2015 Feb 27.

Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2
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.
3
Departments of Molecular and Cellular Biology, and Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
4
Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
5
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.
6
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA dprober@caltech.edu.

Abstract

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.

KEYWORDS:

Hypocretin; Lhx9; Zebrafish

PMID:
25725064
PMCID:
PMC4360184
DOI:
10.1242/dev.117424
[Indexed for MEDLINE]
Free PMC Article

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