Cell Adhesion Molecules during Inner Ear and Hair Cell Development, Including Notch and Its Ligands

Abstract

The vertebrate inner ear develops from a population of placodally derived epithelial cells that initially invaginate to form the otocyst. As development continues, subsets of cells within this population become specified to develop as specific structures within the ear. Subsequently, individual cells undergo morphogenetic and differentiative changes related to the development of specific regions of the ear. The factors that regulate the different developmental events that are required for formation of a complete inner ear are still not completely understood. However, there is growing evidence to suggest that cell–cell adhesion and cell adhesion molecules may play key roles in several aspects of inner ear development.

This chapter summarizes the molecular attributes of the known families of cell adhesion molecules and reviews the existing knowledge about the role of cell adhesion in inner ear development. The roles of cell adhesion in regionalization of the otocyst, cellular differentiation, and neurite extension are reviewed. In addition, the recently demonstrated role of a subset of adhesion molecules, although not necessarily cell–cell adhesion itself, in the development and orientation of hair cell stereociliary bundles is discussed. The role of adhesion molecules in stereociliary bundle development is even more intriguing in light of the fact that many of these molecules were identified as genetic mutations that lead to non-syndromic forms of deafness. These results highlight the importance of adhesion molecules in inner ear development and suggest that the developmental challenges that exist within the inner ear may have resulted in the development of novel functions for adhesion molecules.

Introduction

The vertebrate inner ear is composed of a diverse group of complex structures that includes the semicircular canals, endolymphatic duct, vestibular and auditory sensory epithelia, nonsensory epithelial regions, and vestibular and auditory ganglia. Virtually all of the cells that give rise to these structures derive from the population of epithelial cells that initially comprise the otocyst. During the course of embryogenesis, cells located within the otocyst will be influenced by both intrinsic and extrinsic factors that will regulate multiple aspects of the development of these cells, including cellular proliferation, progressive restriction and ultimate determination of cell fate and differentiation, complex morphogenetic changes, and apoptotic cell death. Despite the recent increase in the number of publications examining different aspects of the development of the inner ear, our understanding of the factors that regulate and coordinate the generation of this elaborate structure is still in its infancy.

A key factor in the formation of any epithelial structure is the ability of individual cells to form adhesive contacts with other cells and with the underlying extracellular matrix. Such adhesive contacts obviously play key roles in the development of specific three-dimensional structures, but more recent results have suggested that cell–cell and cell–basement membrane interactions can also signal within specific cells through the activation of intracellular cascades to initiate cellular responses, including proliferation, determination of cell fate, differentiation, morphogenesis, and both intra- and inter-cellular fasciculation. Classically, cell–cell adhesive interactions were thought to be mediated by either calcium-dependent cadherins or calcium–independent cell adhesion molecules (CAMs), whereas cell–basement membrane interactions were mediated by integrins. However, more recent studies have expanded the spectrum of molecules that can regulate cell adhesion to include claudins, desmosomal cadherins, and protocadherins. Not surprisingly, cell–cell adhesion and adhesion molecules have been shown to play a role in the development of a functional auditory system. But our understanding of the comprehensive role of adhesion in the different steps that must occur between otocyst and mature inner ear is still extremely limited. In this chapter, I will briefly summarize the different families of molecules that have been shown to play a role in cell adhesion and then review the existing data on the role of adhesion in the development of different aspects of the inner ear.