A Notch Affair

Abstract

receptors transmit their signal to the nucleus. Downing StreetThe prevailing models were either that activation results Cambridge, CB2 3DY in the release of a CSL transcription factor from a site England on the intracellular domain of Notch, allowing CSL to translocate to the nucleus and regulate gene expression (Fortini and Artavanis-Tsakonas, 1994), or that activation Poulson first described Drosophila embryos that lacked brings about proteolytic cleavage of Notch, so that an Notch function in 1937 (Poulson, 1937), referring to them intracellular portion of Notch itself moves to the nucleus as "a kind of hopeless monster." Half a century later it and collaborates with CSL to activate transcription (Kois becoming clear how universally important Notch-like pan et al., 1996). Four talks presented evidence in supmolecules are in development, and the discovery that port of the latter model. Raphael Kopan (Washington a late onset disease, CADASIL, is caused by mutations University, St. Louis), who has long been a proponent in Notch 3 suggests these proteins may also have roles of Notch processing, presented data identifying the inin the adult (Joutel et al., 1996). The Drosophila Notch tracellular site of cleavage in mNotch1. Using transgene encodes a 300 kDa receptor, and in spite of the activation of the HES-1 target-gene promoter as an fact that Notch mutations have been around for deassay in cell transfection experiments, he demonstrated cades, there are still many aspects of the structure and that the activation was curtailed when the intracellular function of this receptor and its transmembrane ligands cleavage site was mutated in a transmembrane derivathat remain enigmatic. For example, the extracellular tive of mNotch1. Similar mutations in an mNotch1 derivdomain of Notch contains 36 EGF repeats, but only ative that lacked the transmembrane domain had no two of these (11 and 12) have been assigned a specific effect. Alain Israel (Institut Pasteur, Paris) added further function in ligand binding (Rebay et al., 1991). Furtherdimensions by proposing that there are three sites for more, although transmission of the Notch signal involves processing within the murine Notch1 molecule (Figures a DNA-binding protein that interacts with the intracellu-1B and 1C). The first processing event is due to a constilar domain of Notch (Fortini and Artavanis-Tsakonas, tutive protease pathway that cleaves the protein in the 1994), the mechanisms of activation and transduction extracellular domain, resulting in two fragments that remain controversial. Finally, we are still trying to underhave been observed in previous immunoprecipitation stand what information Notch signaling conveys to the studies (Blaumueller et al., 1997; Pan and Rubin, 1997) cell. These issues are all relevant to the Notch homologs and which remain associated. The enzyme involved is in vertebrates, whose fundamental structure is well conapparently not the ADAM protease Kuzbanian as origiserved (Artavanis-Tsakonas et al., 1995), and to the relanally proposed...

MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling

“…Upon interaction with Delta, Notch is cleaved, allowing the Notch intracellular domain to translocate into the nucleus and regulate gene expression (23). Signaling between neighboring Delta-and Notch-expressing cells is necessary for lateral inhibition and asymmetric cell fates during lineage determination (24)(25)(26) and involves repression of Delta in Notch-expressing cells and similar repression of Notch in adjacent Delta-expressing cells (27)(28)(29)(30)(31)(32)(33). Notch signaling also later regulates differentiation of numerous cell types, including cardial cells (22).…”

Notch activates sonic hedgehog and both are involved in the specification of dorsal midline cell-fates inXenopus

“…Within a proneural cluster, the future neuron is the source of the membrane-bound ligand Delta, which interacts with the receptor Notch on the surface of the neighbouring cells. The receptor is cleaved to render the intracellular domain (Notch ICD ) that enters the nucleus and, in association with CSL intracellular transducers such as Su(H), activates the transcription of target genes that lead to the suppression of the neuronal fate in the cells surrounding the neuronal precursor (Schroeter et al, 1998;Bray, 1998;Wolfe and Haas, 2001;Kopan and Goate, 2002).…”

The Structure and Dynamics of Tandem WW Domains in a Negative Regulator of Notch Signaling, Suppressor of Deltex

“…Su(dx) was identified in Drosophila as a negative regulator of Notch receptor signaling (13)(14)(15)(16). The Notch signal transduction cascade is of fundamental importance for pattern formation and correct execution of multiple cell-fate decisions (17)(18)(19). Direct binding partners for Su(dx) that mediate its effect on Notch signaling are yet to be identified but most probably interact via the Su(dx) WW domains.…”