Cross-regulation of<i>Ngn1</i>and<i>Math1</i>coordinates the production of neurons and sensory hair cells during inner ear development

TLDR

Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis, and the related bHLH genes Ngn1 and Math1 are required respectively for neural and sensory epithelial development in the inner ear. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. We propose that Ngn1 promotes neurogenesis and maintains an uncommitted progenitor pool via Notch‑mediated lateral inhibition, while Math1 irreversibly commits these progenitors to a hair‑cell fate. Cre‑loxP fate mapping shows vestibular sensory hair cells derive from a previously neurogenic region, and analysis of mouse mutants reveals a mutual antagonism between Ngn1 and Math1 that regulates the transition from neurogenesis to sensory cell production, with distinct autoregulatory behaviors—Ngn1 negatively and Math1 positively—driving this switch.

Abstract

Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells derive from a previously neurogenic region of the inner ear. The related bHLH genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and sensory epithelial development in this system. Our analysis of mouse mutants indicates that a mutual antagonism between Ngn1 and Math1 regulates the transition from neurogenesis to sensory cell production during ear development. Furthermore, we provide evidence that the transition to sensory cell production involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1 (positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an uncommitted progenitor cell population through Notch-mediated lateral inhibition, and Math1 irreversibly commits these progenitors to a hair-cell fate.