Effects of the COUP-TFI mutation on murine cochlear function

Abstract

Problem: COUP-TFI (Chicken Ovalbumin Upstream Promoter-Transcription Factor I) is an orphan member of the steroid/thyroid nuclear receptor superfamily. It is highly expressed in the developing nervous system. Null mutant COUP-TFI mice have glossopharyngeal nerve dysfunction that compromises feeding ability and usually results in perinatal death. Surviving null mutant mice demonstrate neuronal differentiation defects, altered thalamocortical axon guidance, and apoptosis of cerebral cortical layer IV. COUP-TFI expression is also important for inner ear organogenesis. Null mutants have a shortened cochlear duct, abnormal cochlear innervation, and malformed vestibular chambers. Additionally, by P20 the organ of Corti in the basal turn has degenerated. Interestingly, the organ of Corti at the mid-modiolar region has only subtle anatomic irregularities and, in particular, contains normal-appearing inner and outer hair cells. We sought to determine the effect of this mutation on cochlear function. Methods: We recorded ABR and DPOAE thresholds in P16-18 null mutant and heterozygote COUP TFI mice, as well as age-matched wild-type controls. ABRs were evoked with a 5 msec sine wave tone pip. DPOAEs were elicited using F2 = 1.2*F1 and L2 = L1. All measurements were performed using stimuli up to 80 dB SPL over the frequency spectrum of 1 to 40 kHz. Results: Null mutant mice had no ABR and no DPOAE responses over the range of stimulation. In contrast, heterozygote and wild-type mice had normal ABR and DPOAE thresholds of 30 to 50 dB in the mid-to-high frequencies. In general, these responses occurred above 6.3 kHz. Conclusion: Both measures of hearing indicate that the COUP-TFI null mutant has profound cochlear dysfunction. Cochlear function in heterozygotes is no different than in wild-type mice. Significance: Even though these mutants have cochleae with many normal anatomic features, these features do not appear to have physiologic relevance. These mutants may be a good model of congenital hearing loss associated with otic capsule malformation. Support: None reported.