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

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Abstract

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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Abbreviations

β Gal:

β Galactosidase

APC:

Adenomatous polyposis coli

ASC:

Aschaete–Scute complex

AtEAM:

Atoh1 E-box associated motif

Ato:

Atonal

bHLH:

Basic helix–loop–helix

EGL:

External germinal layer

HC:

Hair cell

Id:

Inhibitor of differentiation and DNA binding

IHC:

Inner hair cell

ISH:

In situ hybridization

OC:

Organ of Corti

OHC:

Outer hair cell

SC:

Supporting cell

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Acknowledgments

We would like to thank Drs. Jane Johnson, Bernd Fritzsch, Allen Ryan, and Elizabeth Keithley and two anonymous reviewers for their valuable comments and insights. Funding for our work on Atoh1 is provided by an NIH R01 grant (DC011104) and the Shulsky Foundation.

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  1. Division of Otolaryngology, Department of Surgery, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0666, USA

    Joanna Mulvaney & Alain Dabdoub

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  1. Joanna Mulvaney
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  2. Alain Dabdoub
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Correspondence to Joanna Mulvaney or Alain Dabdoub.

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Mulvaney, J., Dabdoub, A. Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency. JARO 13, 281–293 (2012). https://doi.org/10.1007/s10162-012-0317-4

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