title: Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance.
abstract: The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste organs, the fungiform papilla and taste bud, and surrounding lingual cells. Shh signaling has roles in forming and maintaining fungiform papillae and taste buds, most likely via stage-specific autocrine and/or paracrine mechanisms, and by engaging epithelial/mesenchymal interactions.
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hong Xiang
authors.initials: HX
authors.lastname: Liu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ermilov
authors.forename: Marina
authors.initials: M
authors.lastname: Grachtchouk
authors.forename: Libo
authors.initials: L
authors.lastname: Li
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Gumucio
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.forename: Charalotte M
authors.initials: CM
authors.lastname: Mistretta
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002451:Cell Compartmentation; D019070:Cell Lineage; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008024:Ligands; D008648:Mesoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013650:Taste Buds / Q000166:cytology / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
keywords: Fungiform papilla; Gli1; Gli2; Papilla placode; Paracrine signaling; Ptch; Stem cells; Taste cell progenitors
references.citation: Cell. 2012 Feb 3;148(3):608-19
references.pmid: 22304925
references.citation: Nature. 1996 Nov 14;384(6605):176-9
references.pmid: 8906794
references.citation: Dev Biol. 1996 Oct 10;179(1):184-96
references.pmid: 8873763
references.citation: Genes Dev. 2004 Apr 15;18(8):937-51
references.pmid: 15107405
references.citation: Dev Biol. 2004 Dec 15;276(2):280-300
references.pmid: 15581865
references.citation: Future Oncol. 2010 Jun;6(6):1003-14
references.pmid: 20528237
references.citation: Sci Signal. 2012 Oct 16;5(246):re6
references.pmid: 23074268
references.citation: Development. 2002 Oct;129(20):4753-61
references.pmid: 12361967
references.citation: J Neurobiol. 2000 Apr;43(1):98-106
references.pmid: 10756070
references.citation: Cell Mol Life Sci. 2000 Nov;57(12):1672-81
references.pmid: 11130174
references.citation: Cell Stem Cell. 2009 Sep 4;5(3):267-78
references.pmid: 19664980
references.citation: Cell Cycle. 2007 Jan 15;6(2):156-9
references.pmid: 17245127
references.citation: Curr Biol. 1998 Sep 24;8(19):1058-68
references.pmid: 9768360
references.citation: Development. 2010 May;137(10):1586-94
references.pmid: 20430743
references.citation: J Comp Neurol. 1997 Jan 20;377(3):324-40
references.pmid: 8989649
references.citation: Acta Anat (Basel). 1997;160(3):139-58
references.pmid: 9718388
references.citation: J Comp Neurol. 2004 Apr 26;472(2):173-82
references.pmid: 15048685
references.citation: Science. 1997 Aug 22;277(5329):1109-13
references.pmid: 9262482
references.citation: J Clin Invest. 2011 May;121(5):1768-81
references.pmid: 21519145
references.citation: Arch Histol Cytol. 2006 Dec;69(4):199-208
references.pmid: 17287575
references.citation: Differentiation. 1995 Jun;58(5):341-9
references.pmid: 7542613
references.citation: BMC Biol. 2012 Mar 09;10:19
references.pmid: 22405133
references.citation: Stem Cells. 2009 Feb;27(2):442-50
references.pmid: 19038788
references.citation: Development. 2001 Dec;128(24):5161-72
references.pmid: 11748151
references.citation: Dev Biol. 2012 Aug 15;368(2):294-303
references.pmid: 22659543
references.citation: J Neurosci. 1999 Oct 15;19(20):8954-65
references.pmid: 10516314
references.citation: Development. 2013 Jan 15;140(2):255-65
references.pmid: 23250203
references.citation: Dev Biol. 2003 Feb 1;254(1):1-18
references.pmid: 12606278
references.citation: Dev Biol. 2003 Mar 15;255(2):263-77
references.pmid: 12648489
references.citation: J Cell Biol. 1965 Nov;27(2):263-72
references.pmid: 5884625
references.citation: Arch Histol Cytol. 2006 Dec;69(4):209-25
references.pmid: 17287576
references.citation: Development. 2009 May;136(9):1519-28
references.pmid: 19363153
references.citation: Eur J Neurosci. 2010 May;31(9):1549-60
references.pmid: 20525068
references.citation: Mech Dev. 2001 Aug;106(1-2):143-5
references.pmid: 11472844
references.citation: J Cell Sci. 1976 Oct;22(1):149-60
references.pmid: 977666
references.citation: Development. 2006 Mar;133(5):889-900
references.pmid: 16452094
references.citation: J Invest Dermatol. 2000 Nov;115(5):788-94
references.pmid: 11069615
references.citation: Cell Stem Cell. 2011 May 6;8(5):552-65
references.pmid: 21549329
references.citation: Development. 2010 May;137(10):1721-9
references.pmid: 20430747
references.citation: Cell. 2004 Aug 20;118(4):505-16
references.pmid: 15315762
references.citation: Development. 2000 Nov;127(22):4775-85
references.pmid: 11044393
references.citation: Dev Biol. 2006 Sep 1;297(1):198-213
references.pmid: 16828469
references.citation: Neuroscience. 2006 Sep 15;141(4):2129-38
references.pmid: 16843606
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15817-22
references.pmid: 23019366