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

Autor: Caligiuri SPB; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Howe WM; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Wills L; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Smith ACW; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Lei Y; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Bali P; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Heyer MP; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Moen JK; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Ables JL; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Elayouby KS; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Williams M; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Fillinger C; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Oketokoun Z; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Lehmann VE; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., DiFeliceantonio AG; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Johnson PM; Department of Information Technology and Electrical Engineering, ETH Zürich, 8092 Zürich, Switzerland., Beaumont K; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Sebra RP; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Ibanez-Tallon I; Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10065., Kenny PJ; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Nov 15; Vol. 119 (46), pp. e2209870119. Date of Electronic Publication: 2022 Nov 08.
DOI: 10.1073/pnas.2209870119
Abstrakt: 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.
Databáze: MEDLINE
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