Notch signaling: genetics and structure

Abstract

Receptors of the Notch family mediate cell-cell interactions during animal development, and aberrations in Notch signaling have been implicated in human disease. Studies in Caenorhabdits elegans have made essential contributions towards understanding the biological roles and molecular mechanism of this fundamental signaling system. A major development in the field since the original version of this chapter (LIN-12/Notch signaling in C. elegans) has been an explosion in information about the structural biology of Notch signaling; crystallographic determinations of structures, including structures of C. elegans components, have contributed much to the current understanding of molecular mechanism. Thus, here, we not only cover the genetics of Notch in C. elegans, focusing on conserved core components and modulators, we have also included structural information about these components, describing the key events occurring during ligand binding and transcriptional control of target genes. In addition to text, we include Tables listing core components and key modulators of the signaling pathway along with their orthologs in Drosophila and mammals, a Table listing validated target genes in various processes in C. elegans, and animated features to illustrate structural attributes.

A Transparent window into biology: A primer on Caenorhabditis elegans

“…Such screens have been exceptionally useful and informative. For example, lin-12 mutants (C. elegans nomenclature is outlined in Box 1) are defective in vulval development and components of the LIN-12/Notch signaling pathway have been identified with both suppressor and enhancer screens (Greenwald and Kovall 2013).…”

“…Genetic screens in C. elegans have yielded a number of first discoveries of genes and pathways that play important roles in all animals. These discoveries include key genes regulating apoptosis (programmed cell death) (Hedgecock et al 1983;Ellis and Horvitz 1986), the Ras and Notch signaling pathways (Priess 2005;Greenwald and Kovall 2013;Sundaram 2013), synaptic function (Gengyo-Ando et al 1993;Richmond et al 1999), axon pathfinding (Hedgecock et al 1987(Hedgecock et al , 1990, longevity (Kenyon et al 1993;Kimura et al 1997), and developmental timing (the heterochronic genes) (Ambros and Horvitz 1984). The study of the heterochronic genes yielded the first small regulatory RNA, the microRNA (miRNA) product of the lin-4 gene (Lee et al 1993).…”

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

“…ra, right atrium; rv, right ventricle; la, left atrium; lv, left ventricle; as, atrial septum; ct, cushion tissue; ASD, atrial septal defect (*); vs, ventricular septum; vm, ventricular myocardium. expressed in the endocardium and myocardium of Zfp57 A key activation event in NOTCH signaling is ligand-dependent γ-secretase-mediated cleavage of NOTCH receptors (5,6,11,(28)(29)(30). We performed immunostaining with a monoclonal antibody that can only detect the cleaved activated form of NOTCH1 receptor (N1ICD).…”

“…LIN-12/NOTCH signaling is an important pathway in cell-fate specification (5)(6)(7). It is conserved in metazoa from Caenorhabditis elegans to humans (8).…”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…In C. elegans a major function of presenilin is in promoting Notch signaling. Indeed, loss of sel-12 leads to defects in egg laying behavior due to loss of Notch signaling (Greenwald and Kovall, 2013). To determine if Notch or γ-secretase activity has a role in mitochondrial or neurodegenerative phenotype observed in sel-12 mutants, several approaches were taken.…”