In the vestibular system of the inner ear, motion is detected via the mechanical deflection of a bundle of stereocilia located at the top of sensory receptor hair cells. The bundle is morphologically and physiologically polarized because only movements of the bundle towards a lone kinocilium positioned at one side of the apical cell surface are able to produce excitatory responses to acceleration or gravity. Thus the range of motion that can be detected by an individual hair cell is determined by the polarized orientation of the stereociliary bundle. As a result, in order to generate a sensory representation encompassing the broadest possible range of motions, the utricle and saccule contain thousands of vestibular hair cells arranged in radiating arrays spanning a 360? range of bundle orientations. This is achieved in part by dividing the hair cells between two groups separated by a Line of Polarity Reversal (LPR) that have opposing stereocilia bundle orientations and respond to motion in opposite directions. Our goal is to identify the cellular and molecular mechanisms that direct the development of planar polarity and underlie the formation of a sensory representation of gravity and acceleration in the vestibular maculae. This will be addressed through the course of the project using combinations of knockout and transgenic mouse models. Specifically, we will test a hypothesis developed during the first cycle of this grant that two key features organizing planar polarity are established earlier in development than previously expected, and within the otic vesicle. The first of these features is a polarity axis determined by the asymmetric distribution of core PCP proteins in hair cells and supporting cells. Since the formation of this axis is dependent upon the SHH signal transduction molecule Smoothened, we will undertake a series of experiments to determine the mechanisms by which SHH guides planar polarity, distinguishing between instructive and permissive roles. The second feature is a transcriptional boundary established by the transcription factor Emx2 that upon maturation is correlated with the position of the LPR and necessary for its formation. We propose that the emergence of an Emx2 boundary in the otic vesicle precedes formation of the LPR and therefore will identify mechanisms guiding Emx2 expression at early stages of development. Finally, we will determine the mechanisms that allow intercellular PCP signaling and transcriptional boundaries to be maintained throughout morphogenesis in order to understand how these early patterning events might be carried through to the mature sensory organs. Although focused on the development of vestibular planar polarity, we anticipate that this research will impact our understanding of auditory planar polarity as well as other organ systems that rely upon cellular polarization for growth or function.
The polarized development and organization of stereociliary bundles on sensory hair cells of the inner ear underlies the detection of sound and motion, and vestibular hair cell function is important for maintaining balance and posture. This project is designed to determine how stereociliary bundle polarity is established during inner ear development and how hair cells are organized within the utricle and saccule to create a sensory representation of gravity and acceleration. By understanding the developmental events that build the peripheral vestibular system we can predict how they are disrupted in disease states underlying balance disorders and falls, and identity targets for therapeutic intervention.
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