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

Harvard Medical School, Boston, Massachusetts, United States
Development (Impact Factor: 6.46). 01/2008; 134(24):4405-15. DOI: 10.1242/dev.009118
Source: PubMed


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.

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Available from: Steven Raft,
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    • "Both activation and inhibition of Atoh1 require DNA binding and the transcriptional activator function of SOX2 (Neves et al., 2012). Several transcription factors that inhibit Atoh1 expression were found downstream of SOX2, such as ID1–3 (Jones et al., 2006), HES5 (Zine and de Ribaupierre, 2002), HEY1 (Tateya et al., 2011), Neurog1 (Raft et al., 2007), and NeuroD (Jahan et al., 2010) (Table 1, Fig. 2). Among them, Neurog1 is a direct target gene of SOX2 (Jeon et al., 2011), while Ids of BMP signaling (Kamaid et al., 2010), and Hes5 and Hey1 of Notch signaling (Doetzlhofer et al., 2009). "
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    ABSTRACT: Atoh1, Hes1 and Hes5 are crucial for normal inner ear hair cell development. They regulate the expression of each other in a complex network, while they also interact with many other genes and pathways, such as Notch, FGF, SHH, WNT, BMP and RA. This paper summarized molecular pathways that involve Atoh1, Hes1, and Hes5. Some of pathways and gene regulation mechanisms discussed here were studied in other tissues, yet they might inspire studies in inner ear hair cell development. Thereby, we presented a complex regulatory network involving these three genes, which might be crucial for proliferation and differentiation of inner ear hair cells. Copyright © 2014. Published by Elsevier B.V.
    Gene 12/2014; 558(1). DOI:10.1016/j.gene.2014.12.054 · 2.14 Impact Factor
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    • "Combining mouse mutant and genetic reporter analyses, Raft and colleagues (2007) confirmed previous evidence of a rapid and potent positive auto-regulatory activity of Atoh1 in the ear (Helms et al. 2000; Lumpkin et al. 2003). They also provided evidence for Notch-mediated negative autoregulation of Neurog1 (lateral inhibition) in the region of interest (Raft et al. 2007). These results suggested that progenitors expressing a high amount of Neurog1 (Neurog1 high ) have an inhibitory effect on Neurog1 accumulation in their immediate neighbors (Neurog1 low ) before delaminating from the epithelium as committed neural precursors. "
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    ABSTRACT: The vertebrate inner ear is composed of multiple sensory receptor epithelia, each of which is specialized for detection of sound, gravity, or angular acceleration. Each receptor epithelium contains mechanosensitive hair cells, which are connected to the brainstem by bipolar sensory neurons. Hair cells and their associated neurons are derived from the embryonic rudiment of the inner ear epithelium, but the precise spatial and temporal patterns of their generation, as well as the signals that coordinate these events, have only recently begun to be understood. Gene expression, lineage tracing, and mutant analyses suggest that both neurons and hair cells are generated from a common domain of neural and sensory competence in the embryonic inner ear rudiment. Members of the Shh, Wnt, and FGF families, together with retinoic acid signals, regulate transcription factor genes within the inner ear rudiment to establish the axial identity of the ear and regionalize neurogenic activity. Close-range signaling, such as that of the Notch pathway, specifies the fate of sensory regions and individual cell types. We also describe positive and negative interactions between basic helix-loop-helix and SoxB family transcription factors that specify either neuronal or sensory fates in a context-dependent manner. Finally, we review recent work on inner ear development in zebrafish, which demonstrates that the relative timing of neurogenesis and sensory epithelial formation is not phylogenetically constrained.
    Cell and Tissue Research 06/2014; 359(1). DOI:10.1007/s00441-014-1917-6 · 3.57 Impact Factor
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    • "The inner ear stem cells are multipotent and can generate three lineages of pro-sensory, pro-neural and non-sensory cells (Kiernan et al., 2005; Raft et al., 2007, Fig. 2). The pro-sensory cells can be induced into cells that express multiple hair cell markers and functional ion channels specific for nascent hair cells (Li et al., 2003). "
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    ABSTRACT: In mammals, hair cells may be damaged or lost due to genetic mutation, infectious disease, chemical ototoxicity, noise and other factors, causing permanent sensorineural deafness. Regeneration of hair cells is a basic pre-requisite for recovery of hearing in deaf animals. The inner ear stem cells in the organ of Corti and vestibular utricle are the most ideal precursors for regeneration of inner ear hair cells. This review highlights some recent findings concerning the proliferation and differentiation of inner ear stem cells. The differentiation of inner ear stem cells into hair cells involves a series of signaling pathways and regulatory factors. This paper offers a comprehensive analysis of the related studies.
    Developmental Biology 06/2014; 390(2). DOI:10.1016/j.ydbio.2014.03.010 · 3.55 Impact Factor
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