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.
Highlights
During ear development, diverse components of a sensory pathway – neurons, mechanosensory hair cells, supporting cells and other nonsensory epithelial cells – derive from a simple ectodermal placode
Our results indicate that the utricular and saccular maculae, as well as some non-sensory epithelium flanking these structures, derive from the neurogenic region of the otocyst, and that neurogenin 1 (Ngn1)-expressing otocyst cells or their descendants can differentiate as hair cells, supporting cells, or as structural epithelial cells
Math1 suppresses neurogenesis in the developing utricle and saccule Our results indicate that the domain of Ngn1+ precursor cells is gradually transformed from a purely neurogenic region into sensory epithelia of the utricular and saccular maculae
Summary
Diverse components of a sensory pathway – neurons, mechanosensory hair cells, supporting cells and other nonsensory epithelial cells – derive from a simple ectodermal placode. These cell fate decisions are temporally and spatially regulated over a period when the placode, through growth and morphogenesis, transforms into an otocyst and, later, the inner ear labyrinth (see Fig. 1A) (Barald and Kelly, 2004; Kiernan et al, 2002). Hair cells and supporting cells remain epithelial and form six discrete sensory patches along the inner ear labyrinth (Sher, 1971). Five sensory epithelia mediate the sense of balance (the utricular macula, saccular macula, and three cristae) and one – the organ of Corti – detects sound
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