Transcription Factors with Conserved Binding Sites Near ATOH1 on the POU4F3 Gene Enhance the Induction of Cochlear Hair Cells

Ikeda, Ryoukichi; Pak, Kwang; Chávez, Eduardo; Ryan, Allen F.

doi:10.1007/s12035-014-8801-y

Cited by 37 publications

(44 citation statements)

References 54 publications

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“…Therefore, the cell-type-specific cooperation between transcription factors at enhancer regions could explain, at least in part, why Atoh1 exhibits a distinct DNA-binding profile in neurons compared with intestinal cells. For hair cells, analysis of motifs in the enhancers of Atoh1 target genes supports the possibility of it working in combination with other transcription factors to define target gene specificity (42). Heterodimerisation partners also play a role.…”

Section: Interactions Between Transcription Factorsmentioning

confidence: 95%

Atoh1 in sensory hair cell development: constraints and cofactors

Costa

Powell

Lowell

et al. 2017

Seminars in Cell & Developmental Biology

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The proneural gene, Atoh1, is necessary and in some contexts sufficient for early inner ear hair cell development. Its function is the subject of intensive research, not least because of the possibility that it could be used in therapeutic strategies to reverse hair cell loss in deafness. However, it is clear that Atoh1's function is highly context dependent. During inner ear development, Atoh1 is only able to promote hair cell differentiation at specific developmental stages. Outside the ear, Atoh1 is required for differentiation of a variety of other cell types, for example in the intestine and cerebellum. The reasons for this context dependence are poorly understood. So far, the pathways and key players that instruct Atoh1 to act as a mechanosensory cell fate determinant in the context of the inner ear are largely unknown. Here we review evidence that suggests that Atoh1 function in hair cell differentiation is modulated by interaction with other transcription factors. We particularly focus on the possible roles of Gfi1 and Pou4f3, drawing from studies in mouse, Drosophila and C. elegans.3

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Section: Interactions Between Transcription Factorsmentioning

confidence: 95%

Atoh1 in sensory hair cell development: constraints and cofactors

Costa

Powell

Lowell

et al. 2017

Seminars in Cell & Developmental Biology

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“…Pou4f3/ Brn3c/Brn3.1 mutation is associated with hearing loss in humans (Vahava et al 1998) and hair cell loss in mice (Keithley et al 1999). The binding of Atoh1/Math1 to the Pou4f3/Brn3c/Brn3.1 gene enhancer correlates with the induction of hair cells and is reduced by NeuroD/NeuroD1 (Ikeda et al 2014). Among these regulators, NeuroD/ NeuroD1 is also involved in retina development but promotes rather than suppresses sensory receptor development.…”

Section: Sox and Proneural Bhlh Proteins In Neuron And Hair Cell Prodmentioning

confidence: 99%

Can the ‘neuron theory’ be complemented by a universal mechanism for generic neuronal differentiation

Ernsberger

2014

Cell Tissue Res

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With the establishment of the 'neuron theory' at the turn of the twentieth century, this remarkably powerful term was introduced to name a breathtaking diversity of cells unified by a characteristic structural compartmentalization and unique information processing and propagating features. At the beginning of the twenty-first century, developmental, stem cell and reprogramming studies converged to suggest a common mechanism involved in the generation of possibly all vertebrate, and at least a significant number of invertebrate, neurons. Sox and, in particular, SoxB and SoxC proteins as well as basic helix-loop-helix proteins play major roles, even though their precise contributions to progenitor programming, proliferation and differentiation are not fully resolved. In addition to neuronal development, these transcription factors also regulate sensory receptor and endocrine cell development, thus specifying a range of cells with regulatory and communicative functions. To what extent microRNAs contribute to the diversification of these cell types is an upcoming question. Understanding the transcriptional and post-transcriptional regulation of genes coding for cell type-specific cytoskeletal and motor proteins as well as synaptic and ion channel proteins, which mark differences but also similarities between the three communicator cell types, will provide a key to the comprehension of their diversification and the signature of 'generic neuronal' differentiation. Apart from the general scientific significance of a putative universal core instruction for neuronal development, the impact of this line of research for cell replacement therapy and brain tumor treatment will be of considerable interest.

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“…This is thought to be accomplished in part by the action of the mediator complex, proteins that link TFs bound to near and distant regulatory elements to the transcription initiating machinery at the transcription start site or promoter (Poss et al, 2013). To determine whether TFs bound to more distant sites might interact with ATOH1 at the pou4f3 promoter, Ikeda, et al (2014) performed a more detailed analysis of TF binding site conservation in the DNA 5′ to the pou4f3 coding sequence. They identified binding sites for 22 TFs that were highly conserved within the proximal conserved region, the first distal conserved region and the second distal conserved region across the four mammalian species, and that are expressed in the embryonic sensory epithelium (Fig.…”

Section: Regulation Of Pou4f3mentioning

confidence: 99%

“…These were not detected. Although an alternative SOX2 binding site had been identified in distal conserved region 2 of the pou4f3 gene (Ikeda et al, 2014, see Fig. 3), no alternative SIX1 binding sites (Liu et al, 2012) were found to be conserved.…”

Section: Comparison Of Hc Gene Enhancersmentioning

confidence: 99%

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The regulation of gene expression in hair cells

2015

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No genes have been discovered for which expression is limited only to inner ear hair cells. This is hardly surprising, since the number of mammalian genes is estimated to be 20–25,000, and each gene typically performs many tasks in various locations. Many genes are expressed in inner ear sensory cells and not in other cells of the labyrinth. However, these genes are also expressed in other locations, often in other sensory or neuronal cell types. How gene transcription is directed specifically to hair cells is unclear. Key transcription factors that act during development can specify cell phenotypes, and the hair cell is no exception. The transcription factor ATOH1 is well known for its ability to transform nonsensory cells of the developing inner ear into hair cells. And yet, ATOH1 also specifies different sensory cells at other locations, neuronal phenotypes in the brain, and epithelial cells in the gut. How it specifies hair cells in the inner ear, but alternate cell types in other locations, is not known. Studies of regulatory DNA and transcription factors are revealing mechanisms that direct gene expression to hair cells, and that determine the hair cell identity. The purpose of this review is to summarize what is known about such gene regulation in this key auditory and vestibular cell type.

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Transcription Factors with Conserved Binding Sites Near ATOH1 on the POU4F3 Gene Enhance the Induction of Cochlear Hair Cells

Cited by 37 publications

References 54 publications

Atoh1 in sensory hair cell development: constraints and cofactors

Atoh1 in sensory hair cell development: constraints and cofactors

Can the ‘neuron theory’ be complemented by a universal mechanism for generic neuronal differentiation

The regulation of gene expression in hair cells

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