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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Basic Helix-Loop-Helix Transcription Factors / deficiency
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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DNA Primers / genetics
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Ear, Inner / cytology
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Ear, Inner / embryology*
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Ear, Inner / innervation
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Ear, Inner / metabolism
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism
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Female
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Gene Dosage
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Gene Expression Regulation, Developmental
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Green Fluorescent Proteins / genetics
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Hair Cells, Auditory / cytology
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Hair Cells, Auditory / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / cytology
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Neurons / metabolism
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Pregnancy
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Receptors, Notch / metabolism
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Recombinant Fusion Proteins / genetics
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Saccule and Utricle / cytology
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Saccule and Utricle / embryology
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Saccule and Utricle / innervation
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Saccule and Utricle / metabolism
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Signal Transduction
Substances
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Atoh1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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DNA Primers
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Nerve Tissue Proteins
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Receptors, Notch
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Neurog1 protein, mouse