Conditional Deletion of Isl1 Disrupts Cochlear Sensory and Neuronal Development, Leading to Hearing Loss

The molecular mechanisms guiding cochlear development remain incompletely understood. Here, we used conditional deletion mouse models (both sexes) to define the spatiotemporal roles of the transcription factors NEUROD1 and ISL1 during cochlear neurosensory development. Delayed deletion of Neurod1 using Atoh1^Cre had no detectable effect on cochlear structure or hearing function. In contrast, Atoh1^Cre-mediated Isl1 deletion disrupted sensory epithelium organization, producing ectopic inner hair cells and supernumerary outer hair cell rows, and altered spiral ganglion development. Although Atoh1^Cre targeted only a subset of developing spiral ganglion neurons, Isl1 loss resulted in aberrant spiral ganglion morphology, reduced neuronal density, impaired innervation, and defective neuronal migration. These abnormalities arose through a combination of cell-autonomous effects in Isl1-deficient neurons and non-cell-autonomous effects on untargeted, neighboring neurons. The resulting neurosensory abnormalities compromised hearing function, evidenced by elevated auditory brainstem response thresholds, abnormal low-frequency acoustic stimulus processing, and reduced distortion product otoacoustic emissions. Together, these findings further substantiate the essential role of ISL1 in auditory neuron development and establish ISL1 as a key regulator of cochlear neurosensory development.