Journal
GENES & DEVELOPMENT
Volume 27, Issue 5, Pages 565-578Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.207654.112
Keywords
translational profiling; hypocretin; orexin; bacTRAP; Lhx9; narcolepsy
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Funding
- NIH [P30 NS057105]
- Animal Behavior Core [NIH P30 HO062171]
- Clinical Research Training Fellowship from the American Academy of Neurology and American Brain Foundation
- National Institute of Neurological Disorders and Stroke [4R00NS067239-03]
- Mallinckrodt Foundation
- National Human Genome Research Institute [R25 HG006687]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R00AR055948]
- National Institutes of Health [HL 089742]
- Adelson Medical Research Foundation
- Howard Hughes Medical Institute
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Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the molecular phenotype of these cells; previous attempts at comprehensive profiling had only limited sensitivity or were inaccurate. We generated a Hcrt translating ribosome affinity purification (bacTRAP) line for comprehensive translational profiling of all ribosome-bound transcripts in these neurons in vivo. From this profile, we identified >6000 transcripts detectably expressed above background and 188 transcripts that are highly enriched in these neurons, including all known markers of the cells. Blinded analysis of in situ hybridization databases suggests that similar to 60% of these are expressed in a Hcrt marker-like pattern. Fifteen of these were confirmed with double labeling and microscopy, including the transcription factor Lhx9. Ablation of this gene results in a >30% loss specifically of Hcrt neurons, without a general disruption of hypothalamic development. Polysomnography and activity monitoring revealed a profound hypersomnolence in these mice. These data provide an in-depth and accurate profile of Hcrt neuron gene expression and suggest that Lhx9 may be important for specification or survival of a subset of these cells.
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