Notch in vertebrates - molecular aspects of the signal

Abstract

Notch is a receptor consisting of a single path transmembrane protein which is essential for stem cell regulation in both vertebrates and invertebrates. We have investigated the function of Notch signaling and found that ligands of the Notch receptor (Delta and Serrate) sometimes act as receptor modulators in a cell autonomous manner; the balance of their activity as ligands explains satisfactorily 'lateral inhibition' as well as 'lateral specification'. This model explains not only fly morphogenesis, but also the general regulation of stem cells. In vertebrates, members of a novel family of genes which encode small secretory proteins, CCN, were demonstrated to bind to Notch and stimulate signaling. This is not a ligand type binding, but rather a modifier of the protein structure of Notch, so as to form a macromolecular complex. This association may open up novel perspectives on Notch signaling, for instance in the movement of cells involved in somite segmentation or angiogenesis. Thus, a well-conserved signal such as Notch seems to have changed in function during the evolution of vertebrates.

Forkhead family transcription factor FoxO and neural differentiation

“…When Notch signaling is inhibited, the neural stem cells are pushed into the differentiation processes and differentiate into functional cells. The expression level of Notch is elevated on the differentiating neuronal surface; therefore, the differentiation of surrounding cells which also express Notch molecules is inhibited [78]. Presenilin 1 gene-deficient mice have been used to study whether the Notch signaling pathway plays a role in the maintenance of neural stem cell self-renewal.…”

ADAM proteases: ligand processing and modulation of the Notch pathway

“…DSL ligands expressed at high levels act as antagonists of Notch present in the same cell, a cell-autonomous effect known as cis -inhibition [85]. This mode of action of the DSL ligands is best characterized in flies.…”

Notch signalling in cancer stem cells

“…Finally, Notch signalling may involve a number of other proteins such as CCN proteins, which are secreted to the extracellular environment where they may act as regulators of the Notch signal [7].…”

“…In Drosophila, a gene known as Hairy and a gene cluster called Enhancer of split complex (E(spl)-C) are effectors of Notch activation taking part in the development of nervous components as well as in muscle and visceral development. In mammals the Hes (Hairy Enhancer of split) family, composed of seven genes (Hes1- 7), is homologous to the Drosophila Hairy and E(spl)-C. Hes1 plays an important role in nervous system and sensory organ development, as well as in the development of pancreas and other endocrine cells [10]. Hes1 and Hes7 are also involved in somitogenesis and, therefore, in the development of the body pattern [11].…”