Signaling through the Notch receptor protein is used widely in animal development. As discussed in Chapter 22, it has a general role in controlling cell fate choices and regulating pattern formation during the development of most tissues, as well as in the continual renewal of tissues such as the lining of the gut. It is best known, however, for its role in the production of Drosophila neural cells, which usually arise as isolated single cells within an epithelial sheet of precursor cells. During this process, when a precursor cell commits to becoming a neural cell, it signals to its immediate neighbors not to do the same; the inhibited cells develop into epidermal cells instead. This process, called lateral inhibition, depends on a contact-dependent signaling mechanism that is activated by a single-pass trans-membrane signal protein called Delta, displayed on the surface of the future neural cell. By binding to the Notch receptor protein on a neighboring cell, Delta signals to the neighbor not to become neural (Figure 15–58). When this signaling process is defective, a huge excess of neural cells is produced at the expense of epidermal cells, which is lethal.
Notch is a single-pass transmembrane protein that requires proteolytic processing to function. It acts as a latent transcription regulator and provides the simplest and most direct signaling pathway known from a cell-surface receptor to the nucleus. When activated by the binding of Delta on another cell, a plasma-membrane-bound protease cleaves off the cytoplasmic tail of Notch, and the released tail translocates into the nucleus to activate the transcription of a set of Notch-response genes. The Notch tail fragment acts by binding to a DNA-binding protein, converting it from a transcriptional repressor into a transcriptional activator.
The Notch receptor undergoes three successive proteolytic cleavage steps, but only the last two depend on Delta binding. As part of its normal biosynthesis, it is cleaved in the Golgi apparatus to form a heterodimer, which is then transported to the cell surface as the mature receptor. The binding of Delta to Notch induces a second cleavage in the extracellular domain, mediated by an extracellular protease. A final cleavage quickly follows, cutting free the cytoplasmic tail of the activated receptor (Figure 15–59). Note that, unlike most receptors, the activation of Notch is irreversible; once activated by ligand binding, the protein cannot be used again.
This final cleavage of the Notch tail occurs just within the transmembrane segment, and it is mediated by a protease complex called γ-secretase, which is also responsible for the intramembrane cleavage of various other proteins. One of its essential subunits is Presenilin, so called because mutations in the gene encoding it are a frequent cause of early-onset, familial Alzheimer’s disease, a form of presenile dementia. The protease complex is thought to contribute to this and other forms of Alzheimer’s disease by generating extracellular peptide fragments from a transmembrane neuronal protein; the fragments accumulate in excessive amounts and form aggregates of misfolded protein called amyloid plaques, which may injure nerve cells and contribute to their degeneration and loss.
Both Notch and Delta are glycoproteins, and their interaction is regulated by the glycosylation of Notch. The Fringe family of glycosyl transferases, in particular, adds extra sugars to the O-linked oligosaccharide (discussed in Chapter 13) on Notch, which alters the specificity of Notch for its ligands. This has provided the first example of the modulation of ligand–receptor signaling by differential receptor glycosylation.
Wnt Proteins Bind to Frizzled Receptors and Inhibit the Degradation of β-Catenin
Wnt proteins are secreted signal molecules that act as local mediators and morphogens to control many aspects of development in all animals that have been studied. They were discovered independently in flies and in mice: in Drosophila, the Wingless (Wg) gene originally came to light because of its role as a morphogen