Expression of <em>Neurog1</em> Instead of <em>Atoh1</em> Can Partially Rescue Organ of Corti Cell Survival

<div><p>In the mammalian inner ear neurosensory cell fate depends on three closely related transcription factors, <em>Atoh1</em> for hair cells and <em>Neurog1</em> and <em>Neurod1</em> for neurons. We have previously shown that neuronal cell fate can be altered towards hair cell fate by eliminating <em>Neurod1</em> mediated repression of <em>Atoh1</em> expression in neurons. To test whether a similar plasticity is present in hair cell fate commitment, we have generated a knockin (KI) mouse line (<em>Atoh1^KINeurog1</em>) in which <em>Atoh1</em> is replaced by <em>Neurog1</em>. Expression of <em>Neurog1</em> under <em>Atoh1</em> promoter control alters the cellular gene expression pattern, differentiation and survival of hair cell precursors in both heterozygous (<em>Atoh1^+/KINeurog1</em>) and homozygous (<em>Atoh1^{KINeurog1/KINeurog1}</em>) KI mice. Homozygous KI mice develop patches of organ of Corti precursor cells that express <em>Neurog1</em>, <em>Neurod1</em>, several prosensory genes and neurotrophins. In addition, these patches of cells receive afferent and efferent processes. Some cells among these patches form multiple microvilli but no stereocilia. Importantly, <em>Neurog1</em> expressing mutants differ from <em>Atoh1</em> null mutants, as they have intermittent formation of organ of Corti-like patches, opposed to a complete ‘flat epithelium’ in the absence of <em>Atoh1</em>. In heterozygous KI mice co-expression of <em>Atoh1</em> and <em>Neurog1</em> results in change in fate and patterning of some hair cells and supporting cells in addition to the abnormal hair cell polarity in the later stages of development. This differs from haploinsufficiency of <em>Atoh1</em> (<em>Pax2cre; Atoh1^f/+</em>), indicating the effect of <em>Neurog1</em> expression in developing hair cells. Our data suggest that <em>Atoh1^KINeurog1</em> can provide some degree of functional support for survival of organ of Corti cells. In contrast to the previously demonstrated fate plasticity of neurons to differentiate as hair cells, hair cell precursors can be maintained for a limited time by <em>Neurog1</em> but do not transdifferentiate as neurons.</p>