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dc.contributor.authorFreyer, Laina
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 72-07, Section: B, page: 3938.;Advisors: Bernice Morrow.
dc.description.abstractThe inner ear is formed from the otic placode, a specialized region of ectoderm that is induced adjacent to the developing hindbrain. The otic placode invaginates to form the otic vesicle (OV), the primordium of the inner ear labyrinth and cochleovestibular ganglion (CVG). Specification of neuroblasts occurs in the prosensory domain of the OV epithelium and is restricted by the expression of Tbx1, a T-box transcription factor. In Tbx1-/- null mice, the OV fails to undergo morphogenesis and the CVG is duplicated. We are interested identifying upstream and downstream elements of the Tbx1 pathway with respect to neurosensory development of the inner ear.;It has been previously found that Tbx1 functions downstream of the Fibroblast growth factor (Fgf) and Sonic hedgehog (Shh) pathways in the mesenchyme. It remains unknown what regulates Tbx1 in the OV. We hypothesized that canonical Wnt signaling from the hindbrain, acting through nuclear beta-catenin, may directly or indirectly regulate Tbx1 expression in the OV. Conditional beta-catenin gain-of-function (BcatGOF) mice showed loss of Tbx1 expression specifically in the OV. The CVG failed to form in BcatGOF mutants indicating that canonical Wnt signaling regulates neurogenesis independently of Tbx1. We believe that this occurs through the Eya1-Six1 pathway, which promotes survival of CVG neuroblasts and is reduced in BcatGOF mutants.;Haploinsufficiency of TBX1 in humans causes cardiovascular, thymic, craniofacial, and ear defects. These congenital malformations are associated with neural crest cell (NCC) deficiencies. While Tbx1 is not expressed in NCCs, it is known to regulate the migration of NCCS into pharyngeal tissue. A former member of the lab performed genetic fate mapping of the NCC lineage in Tbx1-/- null mice and observed 1) NCC derivatives in the OV and 2) expansion of NCCs in the OV in the absence of Tbx1. This finding was very significant because it is widely accepted that the otic placode is the only source of inner ear epithelial derivatives. Based on these observations, we hypothesized that NCCs migrate to the OV where they participate in neurosensory development and that this process is repressed by Tbx1..;I have defined NCC lineages in the CVG and prosensory epithelia of the inner ear throughout development and into adulthood using Wnt1-Cre and Pax3Cre/+ mice. These cells are distinct from NCC-derived melanocytes that surround the inner ear. I have used time-lapse imaging to document NCCs invading the otic epithelium in vivo. The Wnt1 and Pax3 lineages can give rise to neurons, hair cells, and supporting cells, but not glia. In a sphere-forming assay of adult utricular maculae, I found that the vast majority of spheres contained cells from the NCC lineage. These results demonstrate for the first time a dual origin of the OV and suggest a role for NCCs in maintenance of neurosensory progenitor cells of the inner ear. The mechanism by which Tbx1 represses the contribution of NCCs to the OV remains to be determined.;Many questions remain about direct downstream targets of Tbx1. To help address this, we generated a new GOF allele that conditionally expresses a single copy of Tbx1-GFP driven by the endogenous Rosa26 promoter. Tbx1-GFP is able to rescue the Tbx1-/- null inner ear phenotype in vivo. Ectopic activation of Tbx1-GFP in the olfactory placode represses neurogenesis. This indicates that Tbx1 acts directly on neurogenic factors present in both otic and olfactory epithelia. Persistent expression of Tbx1-GFP in the inner ear causes a delay in semicircular canal formation. We hypothesize that this is due to a novel relationship between Tbx1 and cell adhesion. The Tbx1-GFP mouse line provides a new tool to study tissue-specific targets and functions of Tbx1 in mammalian development.
dc.publisherProQuest Dissertations & Theses
dc.subjectDevelopmental biology.
dc.titleNeurosensory development in the mouse inner ear

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