Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.
Stephanie P B CaligiuriWilliam M HoweLauren WillsAlexander C W SmithYe LeiPurva BaliMary P HeyerJanna K MoenJessica L AblesKarim S ElayoubyMaya WilliamsClementine FillingerZainab OketokounVanessa E LehmannAlexandra G DifeliceantonioPaul M JohnsonKristin BeaumontRobert P SebraInes Ibanez-TallonPaul J KennyPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the <i>Hhip</i> gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.
Keyphrases
- smoking cessation
- single cell
- crispr cas
- replacement therapy
- poor prognosis
- spinal cord
- binding protein
- transcription factor
- copy number
- genome editing
- protein protein
- climate change
- dna binding
- rna seq
- amino acid
- genome wide
- type diabetes
- protein kinase
- long non coding rna
- high throughput
- small molecule
- adipose tissue
- skeletal muscle
- resting state
- genome wide identification
- functional connectivity