Biology Theses and Dissertations

Permanent URI for this collectionhttp://hdl.handle.net/1903/2749

Browse

Filters

2007 - 20082

Settings

Subject: search.filters.subject.hair cells

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    A COMPARATIVE STUDY OF FGFR3 SIGNALING DURING THE DEVELOPMENT OF THE ORGAN OF CORTI AND BASILAR PAPILLA
    (2008-12-11) Jacques, Bonnie E; Jeffery, William R; Kelley, Matthew W; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Most age-related hearing loss is the result of the accumulated death of inner ear hair cells over a life span. Human hair cells lack the ability to be regenerated once they die and thus there is a need to understand the processes which regulate hair cell formation. Unlike the mammalian ear, the avian cochlea has the ability to regenerate lost hair cells and thus there exists an ongoing race to find the key to regeneration in the mammalian ear. Human hearing is dependent on the interactions between numerous cell types yet very little is known about the pathways which regulate the development of the functionally essential support cells of the mammalian cochlear sensory epithelium. This study aims to elucidate some of the genetic pathways involved in hair cell and support cell differentiation in the developing cochlea. Specifically, the role of Fgfr3 signaling in pillar cell and hair cell differentiation will be revealed through the use of an in vivo mutant mouse model containing a null Fgf8 gene and in vitro whole organ culturing of the embryonic cochlear sensory epithelia of mice and chickens. The classic localize, activate, inhibit scheme will be employed. This study will demonstrate that Fgf8 and Fgfr3 are expressed by inner hair cells and pillar cells, respectively, and are required throughout development for normal differentiation and pattern formation of the organ of Corti. Inhibition of the receptor or ligand results in the loss of pillar cells and ectopic formation of hair cells, while activation of this pathway inhibits hair cell formation and induces pillar cells or activation of these genes and their proteins have on the formation of hair cell and support cell types. This study also takes a comparative approach by addressing the similarities and differences of the Fgfr3 signaling pathway in the mammalian organ of Corti and the avian basilar papilla. Fgfr inhibition in the developing basilar papilla causes an increase in hair cell density via the direct transdifferentiation of support cells into hair cells suggesting a role for this signaling pathway in the ability to regenerate hair cells.
  • Thumbnail Image
    Item
    STRUCTURE, LOCALIZATION AND FUNCTION OF MOUSE MYOSIN XVA IN THE INNER EAR
    (2007-01-30) Boger, Erich; Friedman, Thomas B; Popper, Arthur N; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Recessive mutations of MYO15A encoding unconventional myosin XVA are associated with sensorineural deafness in both humans (DFNB3) and the shaker 2 phenotype in mice, which are deaf and exhibit circling behavior due to a vestibular abnormality. Myosin XVa is extensively alternatively spliced and encodes approximately thirty protein isoforms. In mouse hair cells that are homozygous for the shaker 2 (Myo15asupsh2) missense mutation, stereocilia are abnormally short due to a failure of their actin filamentous core to elongate. The stereocilia bundle of homozygous (Myo15asupsh2) hair cells lack the characteristic staircase architecture found in wild type hair cell stereocilia bundles. I show that the inability of mutant myosin XVa to deliver whirlin, a scaffold protein, to stereocilia tips underlies the stereocilia dysmorphology in hair cells from homozygous (Myo15asupsh2) mice. The introduction of exogenous myosin XVa homozygous (Myo15asupsh2) hair cells results in restoration of stereocilia elongation and staircase bundle formation. These results imply that the delivery of whirlin by myosin XVa is essential for stereocilia elongation and staircase formation. Using a series of GFP tagged myosin XVa expression constructs containing deletions of one or more domains, the regions necessary for localization to filopodia tips in COS-7 cells, as a model system, and to stereocilia tips of inner ear hair cells was determined. In COS-7 cells, the myosin XVa motor plus several combinations of domains of the myosin XVa tail are sufficient for filopodia tip targeting. The myosin XVa motor plus either the MyTh4sub1/FERMsub1 or MyTh4sub2/FERMsub2 domains are sufficient for stereocilia tip localization in inner ear hair cells. A preliminary assessment of the regions of myosin XVa necessary for the re-initiation of stereocilia elongation and staircase formation in homozygous (Myo15asupsh2) mutant inner ear hair cells is provided. These results provide a better understanding of the molecular mechanisms underpinning normal stereocilia morphogenesis.