title: Maintenance of Taste Organs Is Strictly Dependent on Epithelial Hedgehog/GLI Signaling.
abstract: For homeostasis, lingual taste papilla organs require regulation of epithelial cell survival and renewal, with sustained innervation and stromal interactions. To investigate a role for Hedgehog/GLI signaling in adult taste organs we used a panel of conditional mouse models to manipulate GLI activity within epithelial cells of the fungiform and circumvallate papillae. Hedgehog signaling suppression rapidly led to taste bud loss, papilla disruption, and decreased proliferation in domains of papilla epithelium that contribute to taste cells. Hedgehog responding cells were eliminated from the epithelium but retained in the papilla stromal core. Despite papilla disruption and loss of taste buds that are a major source of Hedgehog ligand, innervation to taste papillae was maintained, and not misdirected, even after prolonged GLI blockade. Further, vimentin-positive fibroblasts remained in the papilla core. However, retained innervation and stromal cells were not sufficient to maintain taste bud cells in the context of compromised epithelial Hedgehog signaling. Importantly taste organ disruption after GLI blockade was reversible in papillae that retained some taste bud cell remnants where reactivation of Hedgehog signaling led to regeneration of papilla epithelium and taste buds. Therefore, taste bud progenitors were either retained during epithelial GLI blockade or readily repopulated during recovery, and were poised to regenerate taste buds once Hedgehog signaling was restored, with innervation and papilla connective tissue elements in place. Our data argue that Hedgehog signaling is essential for adult tongue tissue maintenance and that taste papilla epithelial cells represent the key targets for physiologic Hedgehog-dependent regulation of taste organ homeostasis. Because disruption of GLI transcriptional activity in taste papilla epithelium is sufficient to drive taste organ loss, similar to pharmacologic Hedgehog pathway inhibition, the findings suggest that taste alterations in cancer patients using systemic Hedgehog pathway inhibitors result principally from interruption of signaling activity in taste papillae.
authors.affiliation: Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Alexandre N
authors.identifier: http://orcid.org/0000-0001-8906-573X
authors.initials: AN
authors.lastname: Ermilov
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Archana
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Libo
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ariell M
authors.identifier: http://orcid.org/0000-0001-9690-5952
authors.initials: AM
authors.lastname: Joiner
authors.affiliation: Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Marina A
authors.identifier: http://orcid.org/0000-0003-4677-2834
authors.initials: MA
authors.lastname: Grachtchouk
authors.affiliation: Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Benjamin L
authors.identifier: http://orcid.org/0000-0003-2323-8313
authors.initials: BL
authors.lastname: Allen
authors.affiliation: Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Andrzej A
authors.identifier: http://orcid.org/0000-0002-9791-3257
authors.initials: AA
authors.lastname: Dlugosz
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Mistretta
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009412:Nerve Fibers / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D013649:Taste / Q000235:genetics*; D013650:Taste Buds / Q000254:growth & development / Q000378:metabolism*; D055697:Taste Perception / Q000235:genetics; D014059:Tongue / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins