Atoh1 as a Coordinator of Sensory Hair Cell Development and Regeneration in the Cochlea

Abstract

Cochlear sensory hair cells (HCs) are crucial for hearing as mechanoreceptors of the auditory systems. Clarification of transcriptional regulation for the cochlear sensory HC development is crucial for the improvement of cell replacement therapies for hearing loss. Transcription factor Atoh1 is the key player during HC development and regeneration. In this review, we will focus on Atoh1 and its related signaling pathways (Notch, fibroblast growth factor, and Wnt/β-catenin signaling) involved in the development of cochlear sensory HCs. We will also discuss the potential applicability of these signals for the induction of HC regeneration.

Keywords: Hair Cells, Auditory; Hearing Loss; Regeneration; Transcription Factors.

FIG. 1. Sensory hair cells in organ of Corti. Inner hair cells are arranged in one row on the medial side of the organ of Corti. Outer hair cells are arranged in three rows on the lateral side. Left side figure is scanning electron microscopy image and right side figure is immunofluorescent image. IHC: inner hair cell, OHC: outer hair cell.

FIG. 2. Atoh1 gene expression during inner ear development. Atoh1 is expressed in the proneuronal cells at E14.5 (A, B) and expressed in sensory hair cells in the cochlea at E16.5 and P1 (C-F). In adult mammals, hair cells are located in the organ of Corti (G, H&E staining) and have stereocillia (H, scanning electro-microscopic image). OHC: outer hair cell, IHC: inner hair cell.

FIG. 3. Notch signaling during mammalian hair cell development. (A) There are 5 notch ligands (Dll1, Dl12, Dll3, jag 1, jag2) in hair cell and 4 notch receptors in the supporting cells. γ-secretase is an internal protease that cleaves the NICD. (B) Notch signaling is activated upon cell-to-cell contact. Downstream genes (Hes1, 5, Hey, other genes) are produced by Notch signaling. These produced inhibitory basic helix-loop-helix proteins (HES1, HES5) blocking the effects of prosenosry genes (Atoh1) that leads to inhibition of the hair cell fate. These inhibited cells differentiate into supporting cells. Dll: delta-like ligand, NICD: notch intracellular domain, CoRs: co-repressor, CSL: CBF1, Su(H) and LAG-1,CoA: co-activator, MAML: mastermind ligand.

FIG. 4. Wnt/β-catenin signaling. Without Wnt ligands, GSK3β complex destructs β-catenin (β-cat) by phosphorylation. This signaling is activated when Wnt ligands bind to Fizzled receptors and their co-receptor lipoprotein receptor-related protein (LRP) 5/6. Subsequently, this lead to sequestration of Axin, recruitment of Disheveled (Dvl), and the release of β-cat. Frizzled receptor is stabilized by attachment of R-spondins (R-spo) to Lgr4/5/6 receptor. Released β-cat is translocated into the nucleus. Ant it will bind to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family to release Wnt target genes, such as Axin2 and Lgr5.

FIG. 5. The proposed Role of Wnt/β-catenin signaling in hair cell regeneration. Wnt/β-catenin signaling can increase hair cell regeneration by stimulating cell mitoic proliferation and up-regulating Atoh1 expression.

FIG. 6. Factors that direct sensory hair cell fate in the inner ear. Beginning at otic placode stages, FGF signaling regulates otic placode development as well as early stage of otocyst formation. A gradient of Wnt signaling determines the size of otic placode. Wnt pathway interacts with notch pathway. FGF signals are upstream activators of Atoh1 genes during the development of prosensory cells. Final sensory hair cell development is regulated by the expression of Atoh1. Supporting cell development is activated by the expression of notch pathway.