<i>Id</i>Gene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling and<i>Atoh1</i>

Kamaid, Andrés; Neves, Joana; Giráldez, Fernando

doi:10.1523/jneurosci.2570-10.2010

Cited by 44 publications

(65 citation statements)

References 59 publications

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“…Bmp signaling influences hair cell differentiation during chicken and mouse inner ear development (70)(71)(72)(73). During zebrafish hair cell regeneration, bmp5 is up-regulated between 1 and 5 h after hair cell death ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

152

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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Section: Resultsmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

152

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“…A DNA mix containing the desired vector(s) mixed with Fast Green was injected onto the otic cup of HH12-14 chick embryos (Neves et al, 2011) or into HH20-21 otic vesicles (Kamaid et al, 2010). Jag1 overexpression in 3-day experiments was confirmed by immunohistochemistry.…”

Section: In Ovo Electroporationmentioning

confidence: 99%

Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

et al. 2014

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During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.

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“…Such interactions would be quite different from BMP's transcriptional activation of Atoh1 in the rhombic lip. In the cochlea, BMP signaling is required for specification of the sensory epithelium (Li et al 2005), but, during HC differentiation, is upstream of Ids 1, 2, and 3, which antagonize Atoh1 activity (Kamaid et al 2010).…”

Section: Post-translational Regulationmentioning

confidence: 99%

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

Mulvaney

Dabdoub

2012

JARO

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Atoh1 (also known as Math1, Hath1, and Cath1 in mouse, human, and chicken, respectively) is a proneural basic helix-loop-helix (bHLH) transcription factor that is required in a variety of developmental contexts. Atoh1 is involved in differentiation of neurons, secretory cells in the gut, and mechanoreceptors including auditory hair cells. Together with the two closely related bHLH genes, Neurog1 and NeuroD1, Atoh1 regulates neurosensory development in the ear as well as neurogenesis in the cerebellum. Atoh1 activity in the cochlea is both necessary and sufficient to drive auditory hair cell differentiation, in keeping with its known role as a regulator of various genes that are markers of terminal differentiation. Atoh1 is known in other fields as an oncogene and a tumor suppressor involved in regulation of cell cycle control and apoptosis. Aberrant Atoh1 activity in adult tissue is implicated in cancer progression, specifically in medullablastoma and adenomatous polyposis carcinoma. We demonstrate through protein sequence comparison that Atoh1 contains conserved phosphorylation sites outside the bHLH domain, which may allow regulation through post-translational modification. With such diverse roles, tight regulation of Atoh1 at both the transcriptional and protein level is essential.

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IdGene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling andAtoh1

Cited by 44 publications

References 59 publications

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

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

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