Cellular organization of the organ of Corti is complex yet precise. Its mechanoreceptive hair cells are arranged such that three rows of outer hair cells and one row of inner hair cells are interdigitated by supporting cells. Disruption of this cellular network causes dysfunction of the organ and thus hearing loss. Multiple developmental pathways have been shown to play important roles during cochlear and hair cell development. The Wnt pathway has been shown to govern hair cell differentiation and patterning, however, the source and identity of secreted Wnts and how secretion are regulated remain incompletely understood. Briefly, a Wnt ligand-producing cell secretes a Wnt protein that is recognized by a Wnt-responsive cell, which expresses membrane bound Wnt receptors, leading to a cellular response. Prior to Wnt secretion, Wnt proteins are lipid modified and transported by the proteins Porcupine (Porcn) and Wntless (Wls), respectively. Here, we propose to ablate Porcn and Wls to characterize their roles during hair cell development. In preliminary experiments, we have observed distinct spatiotemporal expression of Porcn and Wls, and that deletion of these two genes in the Pax2-Cre expression domain leads to distinct phenotypes in the embryonic cochlea. Specifically, Porcn- deficient cochleae were short and contained disorganized hair cells. On the other hand, Wls-deficient inner ear displayed no discernible cochlea. Over three specific aims, we first propose to ablate these two genes using tissue-specific inducible Cre drivers to determine whether they are required for hair cell differentiation and patterning.
In Aim 3, we will characterize the spatio-temporal expression pattern of individual Wnt ligands to identify members expressed in Porcn and Wls-expressing cells. At the completion of these aims, we will have gained a better understanding of the roles of Wnt pathway during embryonic cochlea development and potentially open new exploratory avenues to treat hearing loss.
Hearing loss is the most common sensory disorder in humans, and it can arise from developmental malformations in our hearing organ, the cochlea. Therefore, understanding the development of the cochlea could lead to new hearing loss treatments. This project aims to uncover the roles of the Wnt pathway, an essential developmental pathway, during cochlear development.
| Atkinson, Patrick J; Dong, Yaodong; Gu, Shuping et al. (2018) Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea. J Clin Invest 128:1641-1656 |
| Atkinson, Patrick J; Huarcaya Najarro, Elvis; Sayyid, Zahra N et al. (2015) Sensory hair cell development and regeneration: similarities and differences. Development 142:1561-71 |
