Cellular and Molecular Mechanisms of Ear Morphogenesis

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DESCRIPTION (provided by applicant): The inner ear houses the sensory organs for hearing and balance. Sound is detected in the cochlea; linear acceleration and gravity are sensed in the otolith organs; and angular acceleration is detected in the three semicircular canals, oriented in three orthogonal dimensions. The entire structure arises during development from a simple ball of epithelium, the otic vesicle. Proper auditory and vestibular function therefore relies on the perfect execution of the genetic programs that transform the otic vesicle into the complex labyrinths of the mature inner ear. At a cellular level, morphogenesis of the inner ear involves regulated cell proliferation, apoptosis, and cell-cell interactions. Identification of the ligands and receptors that control these processes in mice may point to new candidate genes and/or therapeutic interventions for inherited inner ear defects in humans. Many forms of human congenital deafness and balance disorders are caused by malformations of the inner ear, which can range from a complete failure to progress beyond the otic vesicle stage to the loss of specific structures such as the cochlea or one semicircular canal. This study examines the contributions of an intriguing family of novel proteins, the Lrigs, to inner ear development. All three Lrigs are proposed to have extracellular domains largely consisting of protein interaction motifs, a single transmembrane domain, and divergent cytoplasmic tails. Lrig3 is required for formation of the lateral semicircular canal in mice. In order to understand the origin and nature of this defect experiments will be performed using mouse genetics, chick embryology, and molecular assays 1) to determine when and where the three Lrig genes are expressed in the ear, 2) to examine in detail the cellular nature of the Lrig3 mutant phenotype and 3) to define the molecular characteristics of this novel protein family, using both in vitro and in vivo assays. Results from these experiments may shed new light on the complicated series of events that are necessary for normal structure and therefore function of the inner ear.