Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Department of Information Technology and Electrical Engineering, ETH Zürich, 8092 Zürich, Switzerland.
Proc Natl Acad Sci U S A. 2022 Nov 15;119(46):e2209870119. doi: 10.1073/pnas.2209870119. Epub 2022 Nov 8.
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 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.
Hedgehog 相互作用蛋白 (HHIP) 将 Hedgehog 配体隔离，以抑制 Smoothened (SMO) 介导的 GLI 家族转录因子的募集。HHIP 的等位基因变异赋予了慢性阻塞性肺疾病和其他与吸烟相关的肺部疾病的风险，但潜在机制尚不清楚。使用单细胞和细胞类型特异性翻译谱分析，我们表明 HHIP 表达在中脑缰核 (MHb) 神经元中高度富集，特别是调节尼古丁引起的厌恶行为反应的 MHb 胆碱能神经元。HHIP 缺乏会使 MHb 中涉及胆碱能信号的基因表达失调，并通过 PTCH-1/胆固醇依赖性机制破坏烟碱型乙酰胆碱受体 (nAChR) 的功能。此外，MHb 神经元中 基因的 CRISPR/Cas9 介导的基因组切割增强了尼古丁在小鼠中的动机特性。这些发现表明，HHIP 通过调节尼古丁对缰核厌恶回路的作用，影响与吸烟相关的肺部疾病的易感性。
