<italic>Math5</italic> expression and function in the central auditory system.

Abstract

The bHLH transcription factor <italic>Math5</italic> (<italic>Atoh7</italic>) is required for retinal ganglion cell and optic nerve development. Using <italic> Math5-lacZ</italic> knockout mice, we have identified additional expression domains for Math5 in functionally connected structures of the central auditory system. In the adult hindbrain, the cytoplasmic <italic>Math5-lacZ</italic> reporter is expressed in the ventral cochlear nucleus (CN), within a subpopulation of neurons that project to medial nucleus of the trapezoid body, lateral superior olive, and lateral lemniscus. These cells were identified as globular and small spherical bushy cells based on their morphology and distribution within the CN, molecular characteristics, and projection patterns. During development, <italic> Math5-lacZ</italic> was detected in precursor cells emerging from the caudal rhombic lip from E 12 onwards, consistent with the time course of CN neurogenesis. The hindbrains of <italic>Math5</italic> mutants appear grossly normal, with the exception of the CN. Although overall CN dimensions are unchanged, the <italic> lacZ</italic> positive cells are significantly smaller in <italic>Math5</italic> -/- mice compared to <italic>Math5</italic> +/- mice, suggesting neuronal dysfunction. The Auditory Brainstem Response (ABR) of <italic>Math5</italic> mutants was evaluated in a BALB/cJ congenic background. ABR thresholds of <italic> Math5</italic> -/- mice were similar to those of wild-type and heterozygous mice, but interpeak latencies for Peaks II-IV were significantly altered. These temporal changes are consistent with a higher level auditory processing disorder involving the CN, potentially affecting the integration of binaural sensory information. BAC transgenic mice that express diphtheria toxin A in the endogenous <italic> Math5</italic> expression pattern were generated to selectively ablate <italic> Math5</italic>-expressing cells in the CN, thereby enhancing the auditory phenotype observed in <italic>Math5</italic> null mice. Preliminary histological analysis of one M5-DTA transgenic line at postnatal day 1 indicates selective elimination of most <italic>Math5</italic>-expressing cells in the retina and CN. Remaining <italic>Math5</italic>-expressing CN neurons have abnormal projection patterns that terminate shortly after exiting the CN and are likely non-functional. <italic>Math5-lacZ</italic> null mice and M5-DTA transgenic mice represent two new models of central auditory dysfunction. Future studies with these models will allow a more detailed understanding of mechanisms underlying anomalies in central auditory processing and may lead to a better understanding and clinical diagnosis of human central auditory pathology.