The mammalian hearing organ, the organ of Corti, consists of precisely patterned one row of inner and three rows of outer sensory hair cells with distinct tissue polarity. Polarity is a feature common to many cell types. Epithelial apical-basolateral polarity enables tissues to perform functions specific for each domain. In addition to this ubiquitous axis of polarization, many epithelial tissues acquire a second polarity axis within the plane of the epithelium, commonly referred as planar cell polarity (PCP). The organ of Corti exemplifies PCP in vertebrates, manifested by uniformly oriented stereocilia on the apical surface of all hair cells. PCP is a fundamental attribute for the structures and functions of the organ of Corti and many other epithelial tissues and organs. However, the underlying molecular mechanisms are largely unknown. Previously, we found that the formation of the uniformly oriented stereocilia (or planar polarization) is accompanied by the tissue extensiong that likely involves a type of cell movement known as convergent extension (CE). This type of cell movement is regulated by a vertebrate pathway homologous to a Drosophila pathway that regulates planar polarization. In addition, we have also found an association of the defect of cochlear extension with the defect of stereocilia orientation in mouse PCP mutants. Therefore, our studies implicated the coupling of the planar polarization with the extension of the organ of Corti by a conserved genetic pathway. In this proposal, we will test the hypothesis that the planar polarization is coupled to CE during terminal differentiation of the organ of Corti by vertebrate PCP pathway.
In Specific Aim I, we will test whether CE occurs during terminal differentiation and whether mutations affecting stereocilia orientation will also affect CE.
In Specific Aim II, we will test whether polarization of PGP components under the influence of morphogen gradients underlies the coupling of CE and stereocilia orientation and explore polarized PCP complexes for our long term goals of dissecting the mammalian PCP pathway. The accomplishment of this proposal will not only have significant contributions to the understanding of the molecular regulation of the growth and patterning of the organ of Corti, but also to the general cell and development biology field. The organ of Corti, with its distinct planar cell polarity, may be the rare and promising opportunity to dissect the intertwined and complex genetic network regulating the formation of this fundamental attribute of many multicellular organs. In addition, since the integrity and polarity of organ of Corti is essential for the function of the cochlea and since convergent extension is essential for gastrulation, our study may also reveal new molecular mechanisms underlying deafness and other birth defects.
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