Notch signaling in the development of the inner ear: Lessons from Drosophila

Abstract

The sensory patches in the ear of a vertebrate can be compared with the mechanosensory bristles of a fly. This comparison has led to the discovery that lateral inhibition mediated by the Notch cell-cell signaling pathway, first characterized in Drosophila and crucial for bristle development, also has a key role in controlling the pattern of sensory hair cells and supporting cells in the ear. We review the arguments for considering the sensory patches of the vertebrate ear and bristles of the insect to be homologous structures, evolved from a common ancestral mechanosensory organ, and we examine more closely the role of Notch signaling in each system. Using viral vectors to misexpress components of the Notch pathway in the chick ear, we show that a simple lateral-inhibition model based on feedback regulation of the Notch ligand Delta is inadequate for the ear just as it is for the fly bristle. The Notch ligand Serrate1, expressed in supporting cells in the ear, is regulated by lateral induction, not lateral inhibition; commitment to become a hair cell is not simply controlled by levels of expression of the Notch ligands Delta1, Serrate1, and Serrate2 in the neighbors of the nascent hair cell; and at least one factor, Numb, capable of blocking reception of lateral inhibition is concentrated in hair cells. These findings reinforce the parallels between the vertebrate ear and the fly bristle and show how study of the insect system can help us understand the vertebrate.

Molecular Genetics of Vestibular Organ Development

“…Experiments designed to block the Notch signaling pathway in the developing chicken inner ears show that Jagged1 expression was down-regulated in the sensory regions rather than up-regulated as the conventional model might have predicted (Haddon et al 1998;Eddison et al 2000). This result suggests that not all Notch ligands respond in a similar manner to changes in Notch signaling.…”

“…The development of the sensory patches in the vertebrate inner ear has been compared with that of the mechanoreceptor organs in fruit flies (Drosophila) (Adam et al 1998;Eddison et al 2000;Fritzsch et al 2000;Caldwell and Eberl 2002). Based on expression studies of Notch signaling molecules, it has been proposed that the expression of Notch ligands, Delta and Jagged/Serrate, on the surface of presumptive sensory hair cells activated Notch receptors present on neighboring cells (Adam et al 1998;Lewis et al 1998).…”

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).…”

“…Together, these data suggest that Hes1 and Hes5 play an anti-neurogenic role for hair cell differentiation. It is hypothesized that Hes1 and Hes5 act downstream of activated Notch pathway (Jarriault et al, 1995;Chen et al, 1997;Lewis, 1998;Ohtsuka et al, 1999;Zine et al, 2001) to prevent the cells surrounding the hair cells from differentiating into the same cell type (Adam et al, 1998;Haddon et al, 1998;Lewis et al, 1998;Lanford et al, 1999;Morrison et al, 1999;Riley et al, 1999;Eddison et al, 2000;Zine et al, 2000;Zhang et al, 2000;Kiernan et al, 2001;Tsai et al, 2001;Kiernan et al, 2005b) and to restrict the boundary of the sensory epithelium (Daudet and Lewis, 2005).…”

Molecular Conservation and Novelties in Vertebrate Ear Development

“…Relying in part on the distribution of Delta and Notch, several investigators (Adam et al, 1998;Eddison et al, 2000) have proposed homology between cells in the insect sensilla and those of the vertebrate ear sensory epithelium. However, this idea does not take the full complement of gene complexity of vertebrates and insects into account .…”