title: The role of Wnt/β-catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line.
abstract: Canonical Wnt/β-catenin signaling has been implicated in multiple developmental events including the regulation of proliferation, cell fate, and differentiation. In the inner ear, Wnt/β-catenin signaling is required from the earliest stages of otic placode specification through the formation of the mature cochlea. Within the avian inner ear, the basilar papilla (BP), many Wnt pathway components are expressed throughout development. Here, using reporter constructs for Wnt/β-catenin signaling, we show that this pathway is active throughout the BP (E6-E14) in both hair cells (HCs) and supporting cells. To characterize the role of Wnt/β-catenin activity in developing HCs, we performed gain- and loss-of-function experiments in vitro and in vivo in the chick BP and zebrafish lateral line systems, respectively. Pharmacological inhibition of Wnt signaling in the BP and lateral line neuromasts during the periods of proliferation and HC differentiation resulted in reduced proliferation and decreased HC formation. Conversely, pharmacological activation of this pathway significantly increased the number of HCs in the lateral line and BP. Results demonstrated that this increase was the result of up-regulated cell proliferation within the Sox2-positive cells of the prosensory domains. Furthermore, Wnt/β-catenin activation resulted in enhanced HC regeneration in the zebrafish lateral line following aminoglycoside-induced HC loss. Combined, our data suggest that Wnt/β-catenin signaling specifies the number of cells within the prosensory domain and subsequently the number of HCs. This ability to induce proliferation suggests that the modulation of Wnt/β-catenin signaling could play an important role in therapeutic HC regeneration.
authors.affiliation: Department of Surgery/Otolaryngology, UCSD School of Medicine, La Jolla, CA, 92093.
authors.forename: Bonnie E
authors.initials: BE
authors.lastname: Jacques
authors.forename: William H
authors.initials: WH
authors.lastname: Montgomery
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Uribe
authors.forename: Andrew
authors.initials: A
authors.lastname: Yatteau
authors.forename: James D
authors.initials: JD
authors.lastname: Asuncion
authors.forename: Genesis
authors.initials: G
authors.lastname: Resendiz
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Matsui
authors.forename: Alain
authors.initials: A
authors.lastname: Dabdoub
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D053403:Lateral Line System / Q000254:growth & development / Q000502:physiology*; D018021:Lithium Chloride / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects; D009925:Organ of Corti / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D055747:SOX Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000819:agonists / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D055747:SOX Transcription Factors; C544611:Sox2 protein, zebrafish; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D018021:Lithium Chloride; D009355:Neomycin
keywords: basilar papilla; hair cell; neuromast; proliferation; regeneration