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Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation

Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Abstract Taste sensation on the anterior tongue requires chorda tympani nerve function and connections with continuously renewing taste receptor cells. However, it is unclear which signaling pathways regulate the receptor cells to maintain chorda tympani sensation. Hedgehog (HH) signaling controls cell proliferation and differentiation in numerous tissues and is active in taste papillae and taste buds. In contrast, uncontrolled HH signaling drives tumorigenesis, including the common skin cancer, basal cell carcinoma. Systemic HH pathway inhibitors (HPIs) lead to basal cell carcinoma regression, but these drugs cause severe taste disturbances. We tested the hypothesis that taste disruption by HPIs reflects a direct requirement for HH signaling in maintaining taste organs and gustatory sensation. In mice treated with the HPI LDE225 up to 28 days, HH-responding cells were lost in fungiform papilla epithelium, and papillae acquired a conical apex. Taste buds were either absent or severely reduced in size in more than 90% of aberrant papillae. Taste bud remnants expressed the taste cell marker keratin 8, and papillae retained expression of nerve markers, neurofilament and P2X3. Chorda tympani nerve responses to taste stimuli were markedly reduced or absent in LDE225-treated mice. Responses to touch were retained, however, whereas cold responses were retained after 16 days of treatment but lost after 28 days. These data identify a critical, modality-specific requirement for HH signaling in maintaining taste papillae, taste buds and neurophysiological taste function, supporting the proposition that taste disturbances in HPI-treated patients are an on-target response to HH pathway blockade in taste organs. hedgehog signaling and taste taste bud and fungiform papillae hedgehog pathway inhibitors cancer drugs and taste sensation chorda tympani nerve responses Copyright © 2015 the American Physiological Society View Full Text Previous Next Back to top View this article with LENS What is LENS? About the Cover About the Cover This is a PDF-only article. The first page of the PDF of this article appears below. Table of Contents Back Matter (PDF) Ed Board (PDF) Keywords hedgehog signaling and taste taste bud and fungiform papillae hedgehog pathway inhibitors cancer drugs and taste sensation chorda tympani nerve responses Article Abstract MATERIALS AND METHODS RESULTS DISCUSSION NOTE ADDED IN PROOF GRANTS DISCLOSURES AUTHOR CONTRIBUTIONS REFERENCES Figures & Data Info E-letters PDF Alert me when this article is cited Alert me if a correction is posted Email Thank you for your interest in spreading the word on Journal of Neurophysiology. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Message Subject (Your Name) has sent you a message from Journal of Neurophysiology Message Body (Your Name) thought you would like to see the Journal of Neurophysiology web site. Your Personal Message Print Citation Tools Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Archana Kumari , Alexandre N. Ermilov , Benjamin L. Allen , Robert M. Bradley , Andrzej A. Dlugosz , Charlotte M. Mistretta Journal of Neurophysiology Feb 2015, 113 (3) 1034-1040; DOI: 10.1152/jn.00822.2014 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Request Permissions Share Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Archana Kumari , Alexandre N. Ermilov , Benjamin L. Allen , Robert M. Bradley , Andrzej A. Dlugosz , Charlotte M. Mistretta Journal of Neurophysiology Feb 2015, 113 (3) 1034-1040; DOI: 10.1152/jn.00822.2014 Permalink: Copy View Full Page PDF Tweet Widget Facebook Like Google Plus One Reddit CiteULike Mendeley StumbleUpon Related Articles Web of Science Scopus PubMed Google Scholar Cited By... Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical usefulness Abstract PDF Receptive field size, chemical and thermal responses, and fiber conduction velocity of rat chorda tympani geniculate ganglion neurons Abstract PDF Fulltext Progress and renewal in gustation: new insights into taste bud development Abstract PDF Fulltext Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma Abstract PDF Fulltext Web of Science (5) Scopus (5) Google Scholar Most Read Most Cited Theories of pain: from specificity to gate control Reward, Motivation, and Emotion Systems Associated With Early-Stage Intense Romantic Love Predictive Reward Signal of Dopamine Neurons Reward, Addiction, and Emotion Regulation Systems Associated With Rejection in Love The organization of the human cerebral cortex estimated by intrinsic functional connectivity More... 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Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation

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References (23)

Publisher
The American Physiological Society
Copyright
Copyright © 2015 the American Physiological Society
ISSN
0022-3077
eISSN
1522-1598
DOI
10.1152/jn.00822.2014
pmid
25392175
Publisher site
See Article on Publisher Site

Abstract

Abstract Taste sensation on the anterior tongue requires chorda tympani nerve function and connections with continuously renewing taste receptor cells. However, it is unclear which signaling pathways regulate the receptor cells to maintain chorda tympani sensation. Hedgehog (HH) signaling controls cell proliferation and differentiation in numerous tissues and is active in taste papillae and taste buds. In contrast, uncontrolled HH signaling drives tumorigenesis, including the common skin cancer, basal cell carcinoma. Systemic HH pathway inhibitors (HPIs) lead to basal cell carcinoma regression, but these drugs cause severe taste disturbances. We tested the hypothesis that taste disruption by HPIs reflects a direct requirement for HH signaling in maintaining taste organs and gustatory sensation. In mice treated with the HPI LDE225 up to 28 days, HH-responding cells were lost in fungiform papilla epithelium, and papillae acquired a conical apex. Taste buds were either absent or severely reduced in size in more than 90% of aberrant papillae. Taste bud remnants expressed the taste cell marker keratin 8, and papillae retained expression of nerve markers, neurofilament and P2X3. Chorda tympani nerve responses to taste stimuli were markedly reduced or absent in LDE225-treated mice. Responses to touch were retained, however, whereas cold responses were retained after 16 days of treatment but lost after 28 days. These data identify a critical, modality-specific requirement for HH signaling in maintaining taste papillae, taste buds and neurophysiological taste function, supporting the proposition that taste disturbances in HPI-treated patients are an on-target response to HH pathway blockade in taste organs. hedgehog signaling and taste taste bud and fungiform papillae hedgehog pathway inhibitors cancer drugs and taste sensation chorda tympani nerve responses Copyright © 2015 the American Physiological Society View Full Text Previous Next Back to top View this article with LENS What is LENS? About the Cover About the Cover This is a PDF-only article. The first page of the PDF of this article appears below. Table of Contents Back Matter (PDF) Ed Board (PDF) Keywords hedgehog signaling and taste taste bud and fungiform papillae hedgehog pathway inhibitors cancer drugs and taste sensation chorda tympani nerve responses Article Abstract MATERIALS AND METHODS RESULTS DISCUSSION NOTE ADDED IN PROOF GRANTS DISCLOSURES AUTHOR CONTRIBUTIONS REFERENCES Figures & Data Info E-letters PDF Alert me when this article is cited Alert me if a correction is posted Email Thank you for your interest in spreading the word on Journal of Neurophysiology. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Message Subject (Your Name) has sent you a message from Journal of Neurophysiology Message Body (Your Name) thought you would like to see the Journal of Neurophysiology web site. Your Personal Message Print Citation Tools Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Archana Kumari , Alexandre N. Ermilov , Benjamin L. Allen , Robert M. Bradley , Andrzej A. Dlugosz , Charlotte M. Mistretta Journal of Neurophysiology Feb 2015, 113 (3) 1034-1040; DOI: 10.1152/jn.00822.2014 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Request Permissions Share Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation Archana Kumari , Alexandre N. Ermilov , Benjamin L. Allen , Robert M. Bradley , Andrzej A. Dlugosz , Charlotte M. Mistretta Journal of Neurophysiology Feb 2015, 113 (3) 1034-1040; DOI: 10.1152/jn.00822.2014 Permalink: Copy View Full Page PDF Tweet Widget Facebook Like Google Plus One Reddit CiteULike Mendeley StumbleUpon Related Articles Web of Science Scopus PubMed Google Scholar Cited By... Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical usefulness Abstract PDF Receptive field size, chemical and thermal responses, and fiber conduction velocity of rat chorda tympani geniculate ganglion neurons Abstract PDF Fulltext Progress and renewal in gustation: new insights into taste bud development Abstract PDF Fulltext Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma Abstract PDF Fulltext Web of Science (5) Scopus (5) Google Scholar Most Read Most Cited Theories of pain: from specificity to gate control Reward, Motivation, and Emotion Systems Associated With Early-Stage Intense Romantic Love Predictive Reward Signal of Dopamine Neurons Reward, Addiction, and Emotion Regulation Systems Associated With Rejection in Love The organization of the human cerebral cortex estimated by intrinsic functional connectivity More... GA_googleFillSlot("JN_tower_right_160x600"); Navigate Current Issue Articles in Press Archives Feedback Submit Subscribe Personal Alerts More Information About this Journal Information for Authors Submit a Manuscript Press Advertising AuthorChoice Calls for Papers Ethics Policy PubMed Central Policy Reprints and Permissions Institutional Administrators APS Publications News Follow APS Publications on Twitter American Physiological Society Journals Cell Physiology Advances in Physiology Education Comprehensive Physiology Endocrinology and Metabolism Gastrointestinal and Liver Physiology Heart and Circulatory Physiology Journal of Applied Physiology Journal of Neurophysiology Lung Cellular and Molecular Physiology Physiological Genomics Physiological Reviews Physiology Regulatory, Integrative and Comparative Physiology Renal Physiology Physiological Reports Legacy Content APS Select www.physiology.org Copyright © 2016 The American Physiological Society | Print ISSN: 0022-3077 | Online ISSN: 1522-1598

Journal

Journal of NeurophysiologyThe American Physiological Society

Published: Feb 1, 2015

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