Hes1andHes5Activities Are Required for the Normal Development of the Hair Cells in the Mammalian Inner Ear

Abstract

The mammalian inner ear contains two sensory organs, the cochlea and vestibule. Their sensory neuroepithelia are characterized by a mosaic of hair cells and supporting cells. Cochlear hair cells differentiate in four rows: a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs). Recent studies have shown that Math1, a mammalian homolog of Drosophila atonal is a positive regulator of hair cell differentiation. The basic helix-loop-helix (bHLH) genes Hes1 and Hes5 (mammalian hairy and Enhancer-of-split homologs) can influence cell fate determination by acting as negative regulators to inhibit the action of bHLH-positive regulators. We show by using reverse transcription-PCR analysis that Hes1, Hes5, and Math1 are expressed in the developing mouse cochleae. In situ hybridization revealed a widespread expression of Hes1 in the greater epithelial ridge (GER) and in lesser epithelial ridge (LER) regions. Hes5 is predominantly expressed in the LER, in supporting cells, and in a narrow band of cells within the GER. Examination of cochleae from Hes1(-/-) mice showed a significant increase in the number of IHCs, whereas cochleae from Hes5(-/-) mice showed a significant increase in the number of OHCs. In the vestibular system, targeted deletion of Hes1 and to a lesser extent Hes5 lead to formation of supernumerary hair cells in the saccule and utricle. The supernumerary hair cells in the mutant mice showed an upregulation of Math1. These data indicate that Hes1 and Hes5 participate together for the control of inner ear hair cell production, likely through the negative regulation of Math1.

Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

“…However, our results show normal expression of Sprouty2. In addition, we found normal expression of Hes5, another gene whose absence causes extra outer hair cells (Zine et al, 2001).…”

“…The other two mouse mutants that give rise to extra outer hair cells are mutants in Hes5 and Sprouty2 (Zine et al, 2001;Shim et al, 2005). We, therefore, looked at the expression of both of these genes in the Fgfr3 mutant animals to ask if changes in these genes are causing the extra hair cell phenotype.…”

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

“…Defects within the notch pathway result in an increase in the number of sensory cell rows of the organ of Corti. In particular, Hes1 mutations cause increases in the number of IHC, whereas Hes5 mutations lead to increased rows of OHCs (Zine et al, 2001). Notch1 mutations lead to increases in both OHC and IHC layers (Hayashi et al, 2008).…”

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

“…The molecular mechanisms underlying the development of the sensory lineage and the patterning of the or-gan of Corti have been studied extensively (Adam et al, 1998;Haddon et al, 1998;Lewis et al, 1998;Lewis, 1998;Bermingham et al, 1999;Lanford et al, 1999Lanford et al, , 2000Morrison et al, 1999;Riley et al, 1999;Eddison et al, 2000;Zhang et al, 2000;Zine et al, 2000Zine et al, , 2001Tsai et al, 2001;Bryant et al, 2002;Chen et al, 2002;Fekete and Wu, 2002;Radde-Gallwitz et al, 2004;Woods et al, 2004;Daudet and Lewis, 2005;Kiernan et al, 2005a,b;Matei et al, 2005). In particular, two classes of basic helix-loop-helix (bHLH)-containing factors, namely the positively and negatively acting transcription factors, have been shown to play essential roles in the differentiation of sensory hair cells and the patterning of the sensory mosaic in the organ of Corti (Bermingham et al, 1999;Zine et al, 2000Zine et al, , 2001Chen et al, 2002;Woods et al, 2004).…”

“…In particular, two classes of basic helix-loop-helix (bHLH)-containing factors, namely the positively and negatively acting transcription factors, have been shown to play essential roles in the differentiation of sensory hair cells and the patterning of the sensory mosaic in the organ of Corti (Bermingham et al, 1999;Zine et al, 2000Zine et al, , 2001Chen et al, 2002;Woods et al, 2004). Math1, a mouse homolog of the Drosophila proneural bHLH gene Atonal, also known as Atoh1 (Atonal homolog 1), is up-regulated within the sensory precursor domain of the cochlea around E13.5-E14.5 (Chen et al, 2002;Woods et al, 2004;Kiernan et al, 2005a;Matei et al, 2005).…”