Understanding the precise patterning of the cochlea across the radial axis is crucial as it confers neural processing by afferent and efferent neurons enabling animals to process sound. An important aspect of this is determining how a pool of progenitors are instructed to differentiate into sub- compartments and several cell types of the cochlea under the control of diffusible factors. Wnts are Bmps are two major families of secreted factors that operate across the radial axis to partition the cochlea and specify cell fates. Wnts are widely known for their ability to re-program quiescent cells to re-enter the cell cycle, but they are also important for cochlear patterning. Our data show that manipulation of Wnt signaling affected cochlear patterning. In the organ of Corti, pharmacological activation of the Wnt pathway on E12.5 cochlear explants showed an increase in the medial compartment and inner hair cells, while suppressing the lateral compartment and outer hair cells. Several known Wnt genes were up regulated at one stage, but were differentially regulated at other stages. This implicates the action of feedback and feedforward networks on target genes. The spatiotemporal expression of target genes, can aid in predicting these gene networks that determine patterning.
Aim 1 will test putative Wnt-mediated gene regulatory networks operating in the cochlea. Activation of the Wnt pathway also repressed Bmp4 expression, which is required for specifying the lateral compartment and fates; thus, the Wnt pathway engages in crosstalk with the Bmp pathway to generate the highly specialized patterning of the organ of Corti.
Aim 2 will investigate molecular mechanisms underlying Wnt-Bmp crosstalk. These studies are specifically designed to identify and validate sub circuits of a larger gene regulatory network regulating radial patterning of the developing mouse cochlea.
The cochlea is an incredibly well designed organ with a specific pattern that dictates our ability to hear. This study will investigate signaling networks by identifying the genes that determine cell fates during early development. These goals will help design strategies to replace damaged cells to cure hearing loss.
