The Notch signaling pathway controls cell fate throughout development in a variety of organisms, from fruit flies to humans. The pathway is crucial for the growth and maturation of numerous systems and organs, including the brain. However, evidence is mounting to suggest that if this pathway goes awry, it contributes to or causes brain tumors, prion disease, multiple sclerosis, and other diseases.
Notch got its name nearly 80 years ago when researchers noticed that some fruit flies (Drosophila melanogaster) had little notches at the ends of their wings, almost as if something had nibbled at them. Over the years, this notched pattern was found to be caused by a single copy of a defective Notch gene. Two defective copies spell death for the developing organism because numerous systems cannot develop without Notch.
Over the years, researchers have learned much about how the Notch gene participates in controlling cell fate. The gene encodes a 300 kDa transmembrane protein embedded in the cell membrane. The extracellular portion of this protein contains a receptor for a number of molecules, or ligands, that have names like Jagged, Delta, and Serrate. When a ligand binds the receptor, a change occurs in the membrane, making the Notch protein susceptible to cleavage by a complex that includes the enzyme γ-secretase. (This enzyme is also involved in producing β-amyloid plaques in Alzheimer’s disease.) When γ-secretase lops off the intracellular portion of Notch, it switches the protein to its active form. The activated Notch then travels to the nucleus, where it binds to DNA to activate a variety of developmental systems. [Eberhart slide 9: Overview of the Notch signaling pathway]
In addition to its role as a gatekeeper of development, the Notch signaling pathway has been implicated in a number of disorders, including cancer, prion diseases, and multiple sclerosis. Notch’s role in these disorders stems from aberrant activation of the pathway. In brain cancer, the Notch signaling pathway sets off the production of proteins that promote unchecked cell renewal. In prion disease, Notch activation causes atrophy of nerve cell dendrites and uncontrolled growth of other brain cells called astrocytes. In multiple sclerosis, Notch sets off an autoimmune attack against the brain via the overproduction of certain immune cells.
Humans have four forms of Notch, and each plays slightly different roles in normal development and in disease. In one part of the developing brain, called the cerebellum, Notch2 has a proliferative effect, whereas Notch1 promotes cell differentiation. Researchers hope that by understanding how the different Notch proteins affect diseases, they can create new treatments for these diseases.
Blockade of the Notch signaling pathway may prove to be one such therapy for Notch-related diseases. The pathway can be stopped by using a drug that inhibits γ-secretase. Because the Notch signaling pathway is used in many organs and systems, however, and because γ-secretase cleaves other proteins in addition to Notch, the potential for side effects is great. Nevertheless, many of the Notch-related diseases are life-threatening and resistant to current therapies, making this research highly promising.
At the April 25, 2006, meeting of the Biochemical Pharmacology Discussion Group, held jointly at the Academy with the New York Section of the American Chemical Society, four researchers working on the Notch signaling pathway spoke on these promising areas of research.
Raphael Kopan of Washington University in St. Louis delivered a short history of Notch biology, and described tools for exploring the role of Notch in the development of the central nervous system and kidneys.
Charles Eberhart of Johns Hopkins University related the role of Notch signaling in the initiation and growth of brain tumors, and described efforts to treat tumors using Notch inhibitors.
Stephen DeArmond of the University of California, San Francisco, presented recent work on the role of Notch signaling in prion disease.
Barbara Osborne of the University of Massachusetts, Amherst, described Notch’s role in the maturation of immune system cells, and discussed whether blocking the pathway could treat autoimmune diseases such as multiple sclerosis.
