Function of the T-box transcription factors Tbx2 and Tbx3 in the development of the murine inner ear

• Applicant: Dr. Mark-Oliver Trowe
• Subject Area: Developmental Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261400253

The inner ear, that mediates the senses of hearing and balance, is characterized by an unusually complex spatial arrangement of numerous highly specialized mechanosensitive cells (hair cells) and non-sensory cell types. In the organ of Corti, the auditory sensory organ located in the cochlea, two different subtypes of hair cells exist that fulfill entirely different functions; inner hair cells are the main sensory cells that convert sound into auditory information, whereas outer hair cells act as mechanical amplifiers that enhance sensitivity to sound and adjust frequency selectivity.The cellular and molecular processes that control the morphogenesis of the inner ear from a simple epithelial vesicle and the differentiation of its constituting cell types from common epithelial progenitors are insufficiently understood. Our preliminary work has shown that the two T-box transcription factor genes Tbx2 and Tbx3 are specifically expressed in diverse sub-regions of the otic epithelium and are crucially required therein for morphogenesis of the vestibular and the auditory system, and the differentiation of inner hair cells in the organ of Corti. Here, we wish to further define the phenotypic requirements of Tbx2 and Tbx3 in inner ear development and identify and characterize the cellular and molecular programs that are regulated by Tbx2 and Tbx3. The specific aims of this proposal are:1. Analysis of Tbx2/Tbx3 function in inner ear morphogenesis in the mouse by phenotypic characterization of mice with conditional loss of Tbx2, Tbx3 and Tbx2/Tbx3 and gain of Tbx2 in the entire otic epithelium, and the identification of downstream effectors of Tbx2 and Tbx3 in this process by microarray and ChIP-seq analysis. 2. Analysis of Tbx2 function in the differentiation of hair and supporting cells from prosensory progenitors during inner ear development in the mouse by phenotypic analysis of conditional mutants with loss and gain of Tbx2 function in prosensory, sensory and non-sensory cells at different stages of organ of Corti development, and the identification of downstream effectors in this process by microarray and ChIP-seq analysis. We expect from these experiments new insight into the cellular and molecular control of inner ear morphogenesis and patterning, and the specification of sensory cells in development and homeostasis. This insight might be useful for future regenerative efforts concerning hair cell loss in human patients.

• DFG Programme: Research Grants