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. Thus the range of motion that can be detected by an individual hair cell is determined by the polarized orientation of the stereocilia bundle. As a result, in order to respond to the broadest range of motions the utricle and saccule contain thousands of vestibular hair cells arranged in radiating arrays spanning a range of nearly 360ps of stereocilia bundle orientations. This is achieved in part by dividing the hair cell between two groups divided by a Line of Polarity Reversal (LPR) that have opposing stereocilia bundle orientations and respond to motions in opposite directions. Our goal is to identify the genetic mechanisms that direct the development of planar polarity. This will be addressed through the course of the project using combinations of knockout and transgenic mouse models. Specifically we will test the hypothesis that the core Planar Cell Polarity (PCP) proteins establis an underlying ground polarity that coordinates the orientation of adjacent hair cells regardless of their position relative to the LPR, and that a second patterning mechanism positions the LPR. For these experiments the significance of the PCP-based ground polarity will be established using a combination of single and double knockouts mouse lines that prevent core PCP signaling. This will complement a genetic dissection of Wnt-signaling and its parallel role in positioning the LPR. Finally, additional factors directing formation of the LPR will be identified through genetic labeling and FACS-based isolation of hair cells with opposite bundle orientations followed by microarray analysis. 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

Public Health Relevance

The polarized development of stereocilia 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 stereocilia bundle polarity is coordinated between adjacent cells in two vestibular organs that detect linear acceleration; the utricle and saccule. By understanding the developmental events that build the peripheral vestibular system we can predict how they are altered in disease states causing balance disorders and falls, and identity targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013066-06
Application #
9231420
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2013-03-25
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
6
Fiscal Year
2017
Total Cost
$284,962
Indirect Cost
$93,712
Name
University of Utah
Department
Surgery
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Stoller, Michelle L; Roman Jr, Orvelin; Deans, Michael R (2018) Domineering non-autonomy in Vangl1;Vangl2 double mutants demonstrates intercellular PCP signaling in the vertebrate inner ear. Dev Biol 437:17-26
Ghimire, Satish R; Ratzan, Evan M; Deans, Michael R (2018) A non-autonomous function of the core PCP protein VANGL2 directs peripheral axon turning in the developing cochlea. Development 145:
Duncan, Jeremy S; Stoller, Michelle L; Francl, Andrew F et al. (2017) Celsr1 coordinates the planar polarity of vestibular hair cells during inner ear development. Dev Biol 423:126-137
Cetera, Maureen; Leybova, Liliya; Woo, Frank W et al. (2017) Planar cell polarity-dependent and independent functions in the emergence of tissue-scale hair follicle patterns. Dev Biol 428:188-203
Goodyear, Richard J; Lu, Xiaowei; Deans, Michael R et al. (2017) A tectorin-based matrix and planar cell polarity genes are required for normal collagen-fibril orientation in the developing tectorial membrane. Development 144:3978-3989
May-Simera, Helen L; Petralia, Ronald S; Montcouquiol, Mireille et al. (2015) Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea. Development 142:555-66
Copley, Catherine O; Duncan, Jeremy S; Liu, Chang et al. (2013) Postnatal refinement of auditory hair cell planar polarity deficits occurs in the absence of Vangl2. J Neurosci 33:14001-16
Deans, Michael R (2013) A balance of form and function: planar polarity and development of the vestibular maculae. Semin Cell Dev Biol 24:490-8