Inactivation of Lats1 and Lats2 highlights the role of hippo pathway effector YAP in larynx and vocal fold epithelium morphogenesis

Mohad, Vidisha; Lungová, Vlasta; Verheyden, Jamie M.; Thibeault, Susan L.

doi:10.1016/j.ydbio.2021.01.012

Cited by 5 publications

(6 citation statements)

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“…In uninfected laryngeal tissues, the proliferation index (% Ki67 + cells) was about 1%. This is consistent with the literature reporting very few proliferating cells in adult mouse vocal folds [ 55 , 57 , 73 ]. Proliferation index increased to a median of 3.4% in diseased murine laryngeal tissues, and Ki67-expressing cells were found above the basal layer of the epithelium.…”

Section: Discussionsupporting

confidence: 93%

“…Vocal fold epithelium is thinner in mice than in humans, comprising 2–4 cell layers rather than 5–10 [ 20 , 54 ]. Likely because of this difference, there is one layer of proliferating basal cells rather than two or three [ 54 , 55 , 56 , 57 ]. The same markers of basal cells (p63), proliferating cells (Ki67), differentiated cells (cytokeratin 13 (K13)), cell–cell junctions (E-cadherin, β-catenin, zonula occludens 1 (ZO-1)), and basement membrane (laminin, collagen IV) are present in the vocal fold epithelium of humans [ 20 , 21 , 22 , 34 , 58 , 59 , 60 ] and mice [ 34 , 47 , 54 , 55 , 56 , 57 , 61 ].…”

Section: Introductionmentioning

confidence: 99%

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Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1

King

Ward-Shaw

et al. 2022

Viruses

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Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1

King

Ward-Shaw

et al. 2022

Viruses

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“…Previous findings from our lab have demonstrated the importance of Hippo/YAP pathway for VF epithelium morphogenesis [ 68 ]. Moreover, Piezo1 and Piezo2 have been implicated as upstream components for signal transduction pathways resulting in YAP transcriptional activity for stem cell differentiation [ 69 ].…”

Section: Resultsmentioning

confidence: 99%

“…Adult VF epithelium expresses mainly cytoplasmic YAP with very few cells exhibiting nuclear expression mainly localized to apical cells (Fig. 7 b) and indicating a role in epithelial cell stratification [ 68 ]. Prior work has also revealed a role for both P63 and YAP in epidermal basal SC proliferation and epithelial stratification [ 70 – 73 ], with additional evidence implicating their genetic interaction in the airway epithelium [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

Piezo1-expressing vocal fold epithelia modulate remodeling via effects on self-renewal and cytokeratin differentiation

Foote

Lungová

Thibeault

2022

Cell. Mol. Life Sci.

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Mechanoreceptors are implicated as functional afferents within mucosa of the airways and the recent discovery of mechanosensitive channels Piezo1 and Piezo2 has proved essential for cells of various mechanically sensitive tissues. However, the role for Piezo1/2 in vocal fold (VF) mucosal epithelia, a cell that withstands excessive biomechanical insult, remains unknown. The purpose of this study was to test the hypothesis that Piezo1 is required for VF mucosal repair pathways of epithelial cell injury. Utilizing a sonic hedgehog (shh) Cre line for epithelial-specific ablation of Piezo1/2 mechanoreceptors, we investigated 6wk adult VF mucosa following naphthalene exposure for repair strategies at 1, 3, 7 and 14 days post-injury (dpi). PIEZO1 localized to differentiated apical epithelia and was paramount for epithelial remodeling events. Injury to wildtype epithelium was most appreciated at 3 dpi. Shhcre/+; Piezo1loxP/loxP, Piezo2 loxP/+ mutant epithelium exhibited severe cell/nuclear defects compared to injured controls. Conditional ablation of Piezo1 and/or Piezo2 to uninjured VF epithelium did not result in abnormal phenotypes across P0, P15 and 6wk postnatal stages compared to heterozygote and control tissue. Results demonstrate a role for Piezo1-expressing VF epithelia in regulating self-renewal via effects on p63 transcription and YAP subcellular translocation—altering cytokeratin differentiation.

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“…The newly separated lamina then fully recanalizes to form a laryngeal lumen that is continuous with the trachea, around which specialized cartilage elements and musculature are specified (Henick, 1993;Lungova et al, 2018Lungova et al, , 2015. Epithelial morphogenesis is genetically dependent upon Wnt, Hippo and HH signaling although the underlying mechanisms remain poorly understood (Lungova et al, 2018(Lungova et al, , 2015Mohad et al, 2021;Tabler et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Hedgehog regulation of epithelial cell state and morphogenesis in the larynx

Ramachandran

Zhou

Bardenhagen

et al. 2022

Preprint

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The larynx enables speech while regulating swallowing and respiration. Larynx function hinges on the laryngeal epithelium which originates as part of the anterior foregut and undergoes extensive remodeling to separate from the esophagus and form vocal folds that interface with the adjacent trachea. Here we find that Sonic hedgehog (SHH) is essential for epithelial integrity in the larynx as well as the anterior foregut. During larynx-esophageal separation, low Shh expression marks specific domains of actively remodeling epithelium that undergo an epithelial to mesenchymal transition (EMT) characterized by the induction of N-Cadherin and movement of cells out of the epithelial layer. Consistent with a role for SHH signaling in regulating this process, Shh mutants undergo an abnormal EMT throughout the anterior foregut and larynx, marked by a cadherin switch, movement out of the epithelial layer and cell death. Unexpectedly, Shh mutant epithelial cells are replaced by a new population of Pax-1 expressing cells that form a rudimentary epithelium. These findings have important implications for interpreting the etiology of HH-dependent birth defects within the foregut. We propose that SHH signaling has a default role in maintaining epithelial identity throughout the anterior foregut and that regionalized reductions in SHH trigger epithelial remodeling.

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Inactivation of Lats1 and Lats2 highlights the role of hippo pathway effector YAP in larynx and vocal fold epithelium morphogenesis

Cited by 5 publications

References 43 publications

Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1

Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1

Piezo1-expressing vocal fold epithelia modulate remodeling via effects on self-renewal and cytokeratin differentiation

Hedgehog regulation of epithelial cell state and morphogenesis in the larynx

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