Coming to Grips with Notch

Notch in Invertebrate Development. Notch proteins are highly conserved transmembrane receptors that are involved in cell fate regulation in invertebrates (1). While Notch receptors are initially synthesized as single polypep-tide chains proteolytic processing results in the formation of a heterodimeric receptor in which the extracellular domain is noncovalently attached to the transmembrane and intracellular (IC) part. The Notch-IC is responsible for sig-naling and contains a series of ankyrin repeats similar to those found in nuclear factor (NF)-␬ B. The ligand-dependent release of Notch-IC requires processing by the membrane associated presenilin which in a mutant form is responsible for familial Alzheimer's disease. The biochemical pathway of Notch-IC dissociation from the receptor is not completely understood but requires at some stage pro-teolytic cleavage (Fig. 1). The Notch receptor ligands include Delta, a transmem-brane protein that affects adjacent cells expressing Notch receptors (2), but may also interact with Notch receptors expressed by the very same cell. Also, soluble Delta ligands have been reported the action of which, however, appears restricted to immediately neighboring cells. The detailed biochemical events that lead to the disso-ciation of Notch-IC from the heterodimeric Notch receptor after ligation are still unknown. There is also relatively little known of how Notch-IC regulates tran-scriptional activity: Notch-IC contains conserved nuclear localization sequences. However, Notch-IC may not directly enter the nucleus but may form a complex with the suppressor of hairless (Su(H)) protein which may function as a transcriptional regulator. Alternatively this complex may allow further posttranslational modifications. What appears to be clear is that only tiny amounts of Notch-IC reach the nucleus. One of the more often discussed modes of Notch activity consists of so-called lateral signaling whereby apparently stochastic small differences of Notch receptors and Delta ligands on apparently otherwise equivalent neighboring cells are exaggerated by feedback loops resulting in cells that either express high levels of Notch receptors or high levels of Delta ligands. Again the biochemistry of these feedback loops is poorly understood. The important point is that the cells with high levels of Notch or high levels of Delta assume different developmental fates (2). However, there are clearly also interactions between Notch receptors and ligands on nonequivalent cells i.e., cells in which the developmental potential differs before the receptor-ligand interaction. Notch in the Mammalian System. In mammals four different Notch receptors (Notch 1–4) and four different ligands (Jagged-1 and-2 as well as Delta-like 1 and 3) have been …