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SOX2 Regulation by Hedgehog Signaling Controls Adult Lingual Epithelium Homeostasis

David Castillo-Azofeifa, Kerstin Seidel, Lauren Gross, Belkis Jacquez, View ORCID ProfileOphir D. Klein, View ORCID ProfileLinda A. Barlow
doi: https://doi.org/10.1101/269522
David Castillo-Azofeifa
1Department of Cell and Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
2Rocky Mountain Taste and Smell Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
3Graduate Program in Cell Biology, Stem Cells and Development, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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Kerstin Seidel
4Program in Craniofacial Biology and Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94131, USA.
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Lauren Gross
1Department of Cell and Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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Belkis Jacquez
1Department of Cell and Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
5BRAIN Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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Ophir D. Klein
4Program in Craniofacial Biology and Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94131, USA.
6Department of Pediatrics, University of California San Francisco, San Francisco, CA 94131, USA.
7Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94131, USA.
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Linda A. Barlow
1Department of Cell and Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
2Rocky Mountain Taste and Smell Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
3Graduate Program in Cell Biology, Stem Cells and Development, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
5BRAIN Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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  • ORCID record for Linda A. Barlow
  • For correspondence: Linda.Barlow@ucdenver.edu
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Abstract

The adult tongue epithelium is continuously renewed from epithelial progenitor cells, and this process relies on intact Hedgehog (HH) signaling. In mice, inhibition of the HH pathway using Smoothened antagonists (HH pathway inhibitors or HPIs) leads to taste bud loss over a span of several weeks. Previously, we demonstrated that overexpression of Sonic Hedgehog (SHH) in lingual epithelial progenitors induces formation of ectopic taste buds accompanied by locally increased SOX2 expression, consistent with the hypothesis that taste bud differentiation depends on SOX2 downstream of HH. To test this idea, we inhibited HH signaling by treating SOX2-GFP mice with HPI and found a rapid and drastic decline in SOX2-GFP expression in taste progenitors and taste buds. Using a conditional Cre-lox system to delete Sox2, we found that loss of SOX2 blocks differentiation of both taste buds and non-taste epithelium that comprises the majority of the tongue surface; progenitor cells increase in number at the expense of differentiated taste cells and lingual keratinocytes. In contrast to the normal pattern of basally restricted proliferation, dividing cells are overabundant, disorganized and present in suprabasal epithelial layers in Sox2 deleted tongues. Additionally, SOX2 loss in taste progenitors leads non-cell autonomously to rapid loss of taste bud cells via apoptosis, dramatically shortening taste cell lifespans. Finally, when Sox2 is conditionally deleted in mice with constitutive overexpression of SHH, ectopic taste buds fail to form and endogenous taste buds disappear; instead, robust hyperproliferation takes over the entire lingual epithelium. In sum, our experiments suggest that SOX2 functions downstream of HH signaling to regulate lingual epithelium homeostasis.

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Posted February 22, 2018.
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SOX2 Regulation by Hedgehog Signaling Controls Adult Lingual Epithelium Homeostasis
David Castillo-Azofeifa, Kerstin Seidel, Lauren Gross, Belkis Jacquez, Ophir D. Klein, Linda A. Barlow
bioRxiv 269522; doi: https://doi.org/10.1101/269522
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SOX2 Regulation by Hedgehog Signaling Controls Adult Lingual Epithelium Homeostasis
David Castillo-Azofeifa, Kerstin Seidel, Lauren Gross, Belkis Jacquez, Ophir D. Klein, Linda A. Barlow
bioRxiv 269522; doi: https://doi.org/10.1101/269522

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