Notch receptors are a family of proteins located on the surface of cells that are involved in communication between adjacent cells. This signaling system is highly conserved across most animals and plays a role in guiding how cells develop and function. Their presence and activity are widespread across numerous tissues and developmental stages, from the embryo to the adult.
Structure and Activation of Notch Receptors
Notch receptors are single-pass transmembrane proteins, meaning they cross the cell’s outer membrane once. Their structure consists of a large extracellular portion, a segment that spans the membrane, and an intracellular domain. In mammals, there are four distinct Notch receptors (NOTCH1-4) that interact with ligands from the Delta-like (DLL) and Jagged (JAG) families on an adjacent cell.
The activation of the Notch pathway is a precisely regulated process that involves sequential proteolytic cleavages. When a ligand on one cell binds to the Notch receptor on another, it induces a physical pulling force. This force causes a conformational change in the receptor, exposing a cleavage site known as S2. An enzyme called ADAM metalloprotease then cuts the receptor at this site.
This initial cut triggers a second cleavage event within the transmembrane domain, at a site designated S3, which is carried out by a protein complex called gamma-secretase. This final cut liberates the Notch Intracellular Domain (NICD) from the cell membrane. Once freed, the NICD travels to the cell’s nucleus. In the nucleus, NICD binds to the DNA-binding protein CSL and recruits co-activators like Mastermind-like proteins to turn on the expression of specific target genes, such as those in the Hes and Hey families.
Cellular Processes Regulated by Notch Signaling
The activation of Notch target genes has consequences at the cellular level, influencing behaviors and decisions. One of the roles of Notch signaling is in cell fate determination. This is often achieved through a mechanism called lateral inhibition, where one cell adopts a specific fate and simultaneously signals its immediate neighbors to prevent them from adopting the same identity, thereby promoting diversity within a tissue.
Notch signaling also regulates cell proliferation. Its effect can be context-dependent, either promoting or inhibiting cell division to ensure that tissues grow to the correct size and maintain proper cell numbers. For instance, in some cancer cells, Notch can drive proliferation, while in other contexts, like among neural progenitor cells, it can halt the cell cycle.
The pathway is also involved in managing the balance between maintaining populations of stem or progenitor cells and pushing them toward differentiation into specialized cell types. This regulation ensures a continuous supply of new cells for tissue maintenance and repair. Notch signaling also influences apoptosis, or programmed cell death, by regulating genes that promote or inhibit cell survival, which helps remove unnecessary or damaged cells.
Notch Signaling in Organismal Development
The cellular functions governed by Notch signaling are integrated to orchestrate the development and maintenance of entire organs and tissues. For example, in the developing nervous system, or neurogenesis, Notch helps maintain populations of neural stem cells and plays a part in the decision for a progenitor cell to become a neuron or a supportive glial cell.
During cardiovascular development, Notch signaling is active in the formation of new blood vessels (angiogenesis). It also contributes to the proper development of the heart and its valves. Another example is somitogenesis, the process where the embryonic mesoderm is segmented into blocks called somites, which later give rise to the vertebrae, ribs, and skeletal muscle. This segmentation relies on oscillatory patterns of Notch activity.
The pathway also has a defined role in hematopoiesis, the development of blood cells. It is particularly important for the development of T-cells, a type of white blood cell, within the thymus. In the developing gut, Notch signaling is responsible for the correct patterning and differentiation of the various cell types that make up the intestinal lining.
Notch Signaling Dysregulation and Disease
Dysregulation of Notch signaling, either through excessive or insufficient activity, is linked to a range of human diseases. In the context of cancer, aberrant Notch signaling can act as either an oncogene, promoting tumor growth, or a tumor suppressor, depending on the cellular environment. One of the most prominent examples is T-cell Acute Lymphoblastic Leukemia (T-ALL), where mutations that activate the NOTCH1 receptor are very common. The pathway is also implicated in solid tumors, including breast, lung, and colon cancers.
Mutations in genes that encode components of the Notch pathway can also lead to developmental disorders. Alagille syndrome, for instance, is caused by mutations in either JAG1 or NOTCH2 and affects the development of the liver, heart, and other organs. Another genetic disorder, CADASIL, results from mutations in the NOTCH3 gene and leads to strokes and dementia in adults.
Beyond cancer and congenital disorders, the dysregulation of Notch signaling can impact the immune system. The pathway’s role in T-cell development means that improper signaling can affect immune cell function and contribute to various immune-related conditions.