Eddison, Mark Keith Lang; (2001) Notch signaling in the development of the inner ear. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The sensory patches of the inner ear consist of two types of cell: sensory hair cells and supporting cells. The pattern is such that supporting cells surround each hair cell and no two hair cells touch each other. The aim of this study was to uncover the genetic mechanisms that control the differentiation and patterning of these two cell types. The alternating pattern of hair cells and support cells has led to the suggestion that their differentiation is co-ordinately regulated by cell- cell interactions involving the Notch signaling pathway. The key players in this pathway are Delta, a ligand, and Notch, its receptor, mediating a process known as lateral inhibition - a mechanism which forces neighbouring cells of an initially equivalent group to become different. The findings in this study show that two Notch ligands Deltal and Serrate2 are expressed in the nascent hair cells and are thought to deliver lateral inhibition to their neighbours, which become supporting cells. Intriguingly, the supporting cells also express a Notch ligand, Serratel. To functionally test the role of the Notch signaling pathway in the developing chick inner ear, retroviral vectors were used to misexpress components of the Notch signaling pathway. It is shown that a simple lateral inhibition model based on feedback regulation of the Notch ligands is inadequate to explain the generation and patterning of the sensory hair cells. The Notch ligand Serratel is regulated by lateral induction and not lateral inhibition; commitment to become a hair cell is not simply controlled by levels of expression of the Notch ligand Deltal, Serratel, and Serrate2 in the neighbours of the nascent hair cell. At least one factor. Numb, capable of blocking reception of Notch signaling is concentrated in hair cells.

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