Generation of mice with inducible Cre expression in adult cochlear hair cells

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DESCRIPTION (provided by applicant): Our ability to manipulate gene expression specifically in the hair cells of the inner ear during development and adulthood in mice is crucial for understanding the physiology of hearing and the pathology of deafness in humans. Recent advances from our laboratory and many others have demonstrated that gene expression can be manipulated in developing mouse hair cells in a spatially and temporally controlled manner. However, a key feature remains elusive -- our ability to manipulate gene expression specifically in mature inner hair cells (IHCs) and outer hair cells (OHCs). Here we propose to develop transgenic or knockin mice that express inducible CreERT2, an effective fusion of Cre and estrogen receptor (CreER), in mature cochlear hair cells (OHCs in Aim 1; IHCs and OHCs in Aim 2). The characterization and availability of these mouse lines will enable auditory researchers to inactivate or activate genes of their interest in mature hair cells. The creation of conditional (loxP) alleles of every mouse gene in their genome, which has been proposed in the NIH's Knockout Mouse Project (KOMP), will provide a complementary resource for the use of the inducible Cre lines that we generate. Finally, the strategies we adopt here can be used to express genes specifically in other mature cell types of the inner ear (i.e., IHCs, spiral ganglia, stria fibrocytes and marginal cells) at any given time. All mouse lines will be genetically engineered in 129S7/C57BL/6J mixed or FVB/NJ strains, transferred to the CBA/CaJ strain, and then deposited in the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC). Public Health Relevance Statement An estimated 28 million people in the United States are deaf or hard of hearing. Approximately 1.5 million individuals aged 3 years or older are deaf in both ears and 2 to 3 per 1,000 live births suffer congenital hearing loss. More than 40 million persons in the United States suffer various levels of noise induced hearing loss. Despite the significant progress in our understanding of these hearing disorders, very little is known about the disease causes and about the normal hearing processes in adults. Many genetic factors (genes) that, when mutated, cause hearing impairment in people, play critical roles in both infants and adults. We propose here to develop genetic tools that would allow us to investigate the function of hearing related genes in adult animal models. These tools will be able to surgically activate genes in a specific set of cells in the hearing process at any time of the adult life of the animal. This temporal and spatial precision is critical for our understanding of hearing process and developing therapeutic targets for intervention of the hearing disorders.