Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

Mulvaney, Joanna F.; Dabdoub, Alain

doi:10.1007/s10162-012-0317-4

Cited by 96 publications

(95 citation statements)

References 89 publications

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“…By contrast, we show here that the combination of Atoh1 with Gfi1 and Pou4f3 leads to the implementation of a HC differentiation program in EB cells, as well as in non-sensory otic epithelia. These findings unveil a novel regulatory layer in HC fate specification and provide a molecular basis to explain how Atoh1 can induce different cell fates in the embryo -not only HCs in the inner ear, but also Merkel cells in the skin, secretory cells in the intestine, or granule neurons in the cerebellum (Mulvaney and Dabdoub, 2012).…”

Section: Combinatorial Transcriptional Control Of Hc Formationmentioning

confidence: 81%

Generation of sensory hair cells by genetic programming with a combination of transcription factors

et al. 2015

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Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. Elucidation of the transcriptional networks regulating HC fate determination and differentiation is crucial not only to understand inner ear development but also to improve cell replacement therapies for hearing disorders. Here, we show that combined expression of the transcription factors Gfi1, Pou4f3 and Atoh1 can induce direct programming towards HC fate, both during in vitro mouse embryonic stem cell differentiation and following ectopic expression in chick embryonic otic epithelium. Induced HCs (iHCs) express numerous HC-specific markers and exhibit polarized membrane protrusions reminiscent of stereociliary bundles. Transcriptome profiling confirms the progressive establishment of a HC-specific gene signature during in vitro iHC programming. Overall, this work provides a novel approach to achieve robust and highly efficient HC production in vitro, which could be used as a model to study HC development and to drive inner ear HC regeneration.

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Section: Combinatorial Transcriptional Control Of Hc Formationmentioning

confidence: 81%

Generation of sensory hair cells by genetic programming with a combination of transcription factors

et al. 2015

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“…For example, Drosophila atonal plays a role in the formation of chordotonal organs (stretch receptors), photoreceptors, some olfactory receptors, and a single neural lineage in the brain (Jarman et al, 1993a; 1994; Gupta and Rodrigues, 1997; Hassan et al, 2000); other parts of the nervous system do not express or require the gene. A similarly restricted function can be attributed to the mouse atonal homologs (e.g., Atoh1, Atoh5 ; reviewed in Hsiung and Moses, 2002; Quan and Hassan, 2005; Mulvaney and Dabdoub, 2012). Secondly, different proneural genes may act sequentially in the same proneural cluster in a cascade, whereby an early expressed proneural gene directly promotes the transcription of a later one.…”

Section: Discussionmentioning

confidence: 94%

bHLH proneural genes as cell fate determinants of entero-endocrine cells, an evolutionarily conserved lineage sharing a common root with sensory neurons

Hartenstein

Takashima

Hartenstein

et al. 2017

Developmental Biology

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Entero-endocrine cells involved in the regulation of digestive function form a large and diverse cell population within the intestinal epithelium of all animals. Together with absorptive enterocytes and secretory gland cells, entero-endocrine cells are generated by the embryonic endoderm and, in the mature animal, from a pool of endoderm derived, self-renewing stem cells. Entero-endocrine cells share many structural/functional and developmental properties with sensory neurons, which hints at the possibility of an ancient evolutionary relationship between these two cell types. We will survey in this article recent findings that emphasize the similarities between entero-endocrine cells and sensory neurons in vertebrates and insects, for which a substantial volume of data pertaining to the entero-endocrine system has been compiled. We will then report new findings that shed light on the specification and morphogenesis of entero-endocrine cells in Drosophila. In this system, presumptive intestinal stem cells (pISCs), generated during early metamorphosis, undergo several rounds of mitosis that produce the endocrine cells and stem cells (ISCs) with which the fly is born. Clonal analysis demonstrated that individual pISCs can give rise to endocrine cells expressing different types of peptides. Immature endocrine cells start out as unpolarized cells located basally of the gut epithelium; they each extend an apical process into the epithelium which establishes a junctional complex and apical membrane specializations contacting the lumen of the gut. Finally, we show that the Drosophila homolog of ngn3, a bHLH gene that defines the entero-endocrine lineage in mammals, is expressed and required for the differentiation of this cell type in the fly gut.

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“…Previous studies on Atoh1 function in the cochlea focused mainly on the regulation of hair cell differentiation (Mulvaney and Dabdoub, 2012). However, the sustained expression of Atoh1 in differentiating hair cells until after birth suggests Atoh1 might also participate in other biological programs involved in the maturation and function of hair cells.…”

Section: The Role Of Atoh1 In Hair Bundle Development and Functionmentioning

confidence: 99%

Conditional Deletion of Atoh1 Reveals Distinct Critical Periods for Survival and Function of Hair Cells in the Organ of Corti

Cai¹,

Seymour

Zhang³

et al. 2013

Journal of Neuroscience

118

149

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Atonal homolog1 (Atoh1) encodes a basic helix-loop-helix protein that is the first transcription factor to be expressed in differentiating hair cells. Previous work suggests that expression of Atoh1 in prosensory precursors is necessary for the differentiation and survival of hair cells, but it is not clear whether Atoh1 is required exclusively for these processes, or whether it regulates other functions later during hair cell maturation. We used EGFP-tagged Atoh1 knock-in mice to demonstrate for the first time that Atoh1 protein is expressed in hair cell precursors several days before the appearance of differentiated markers, but not in the broad pattern expected of a proneural gene. We conditionally deleted Atoh1 at different points in hair cell development and observe a rapid onset of hair cell defects, suggesting that the Atoh1 protein is unstable in differentiating hair cells and is necessary through an extended phase of their differentiation. Conditional deletion of Atoh1 reveals multiple functions in hair cell survival, maturation of stereociliary bundles, and auditory function. We show the presence of distinct critical periods for Atoh1 in each of these functions, suggesting that Atoh1 may be directly regulating many aspects of hair cell function. Finally, we show that the supporting cell death that accompanies loss of Atoh1 in hair cells is likely caused by the abortive trans-differentiation of supporting cells into hair cells. Together our data suggest that Atoh1 regulates multiple aspects of hair cell development and function.

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Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

Cited by 96 publications

References 89 publications

Generation of sensory hair cells by genetic programming with a combination of transcription factors

Generation of sensory hair cells by genetic programming with a combination of transcription factors

bHLH proneural genes as cell fate determinants of entero-endocrine cells, an evolutionarily conserved lineage sharing a common root with sensory neurons

Conditional Deletion of Atoh1 Reveals Distinct Critical Periods for Survival and Function of Hair Cells in the Organ of Corti

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