Hedgehog-interacting protein acts in the habenula to regulate nicotine intake

Stephanie P.B. Caligiuri, William M. Howe, Lauren Wills, Alexander C.W. Smith, Ye Lei, Purva Bali, Mary P. Heyer, Janna K. Moen, Jessica L. Ables, Karim S. Elayouby, Maya Williams, Clementine Fillinger, Zainab Oketokoun, Vanessa E. Lehmann, Alexandra G. DiFeliceantonio, Paul M. Johnson, Kristin Beaumont, Robert P. Sebra, Ines Ibanez-Tallon, Paul J. Kenny

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 Hhip 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.

Original languageEnglish
Article numbere2209870119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - 15 Nov 2022


  • chronic obstructive pulmonary disease
  • habenula
  • hedgehog signaling
  • nicotine
  • single-cell RNA sequencing


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