Delta-Notch signaling is a fundamental cell-to-cell communication pathway found across multicellular organisms. This system guides individual cells in making decisions, such as whether to specialize into a particular tissue type or maintain a more versatile, stem-like state. By orchestrating these cellular choices, Delta-Notch signaling plays a broad role in shaping an organism’s development and ensuring the proper function of its tissues throughout life.
How Cells Communicate Through Delta Notch
Cells employ Delta-Notch signaling through direct physical contact, known as juxtacrine signaling. This interaction involves two adjacent cells: a “signal-sending” cell displaying a protein called Delta on its surface, and a “signal-receiving” cell equipped with a Notch receptor. The Notch receptor spans the cell membrane, with an extracellular part, a transmembrane segment, and an intracellular domain.
When the Delta protein on one cell binds to the Notch receptor on a neighboring cell, it triggers molecular events within the signal-receiving cell. This binding causes a structural change in the Notch receptor, making it accessible to specific enzymes. First, an enzyme called ADAM metalloprotease cleaves the Notch receptor just outside the cell membrane, releasing its extracellular portion.
Following this initial cleavage, another enzyme complex, gamma-secretase, performs a second cut within the Notch receptor’s transmembrane domain. This second cleavage liberates the Notch Intracellular Domain (NICD). Once freed, the NICD travels from the cell membrane into the cell’s nucleus.
Inside the nucleus, the NICD forms a complex with other proteins, including the CSL transcription factor and Mastermind-like (MAML) proteins. This complex then binds to specific DNA sequences, turning on or off particular target genes. By regulating gene expression, Delta-Notch signaling influences the cell’s behavior, guiding its developmental path or maintaining its current state.
Critical Roles in Body Development and Function
Delta-Notch signaling is an ancient pathway, conserved across many animal species, and it orchestrates numerous processes from the earliest stages of life through adulthood. During embryonic development, this pathway is instrumental in guiding cells to form complex structures and specialized tissues. For example, it plays a part in neurogenesis, the process where neurons differentiate and the nervous system forms, by influencing the proliferation of precursor cells and directing them towards either neuronal or glial cell fates.
The pathway also contributes to somitogenesis, the formation of segmented blocks of tissue called somites, which later give rise to structures like vertebrae and muscles. In the developing cardiovascular system, Delta-Notch signaling is involved in cardiogenesis, the formation of the heart, and in vasculogenesis and angiogenesis, which are the processes of forming and maturing blood vessels. This signaling helps stabilize the identity of arterial endothelial cells, which line blood vessels.
Beyond development, Delta-Notch signaling continues to be active in maintaining the health and function of adult tissues. It helps regulate tissue homeostasis, ensuring that tissues like the intestinal lining, skin, and blood maintain their integrity and replace old or damaged cells. The pathway is particularly significant in guiding stem cell decisions, balancing their ability to self-renew with their differentiation into specific cell types needed for tissue repair and regeneration. For instance, Notch1 and Notch2 are involved in specifying the fate of absorptive cells in intestinal stem cells.
In the bone marrow, Delta-Notch signaling contributes to hematopoiesis, the continuous production of all types of blood cells. The precise control exerted by this pathway ensures that the right number and type of cells are produced at the correct time and place, supporting the body’s ongoing needs. This broad involvement highlights the pathway’s fundamental importance in sustaining life and enabling proper biological function across different systems.
When Delta Notch Signaling Goes Wrong
When Delta-Notch signaling is disrupted, it can lead to various diseases and developmental disorders. These disruptions can result from genetic mutations in the components of the pathway, altering how cells communicate and make decisions.
One notable example of a developmental disorder linked to faulty Delta-Notch signaling is Alagille syndrome (ALGS), an autosomal dominant condition affecting multiple organ systems. The majority of ALGS cases, about 94%, are caused by mutations in the JAG1 gene, which encodes a Notch ligand, while a smaller percentage, approximately 2%, involve mutations in the NOTCH2 receptor gene. These loss-of-function mutations lead to abnormalities in the liver, often presenting as bile duct paucity and cholestasis, alongside issues in the heart, eyes (like posterior embryotoxon), spine (such as butterfly vertebrae), and kidneys. Patients with ALGS often exhibit characteristic facial features, including a broad forehead, deep-set eyes, and a pointed chin, creating a triangular appearance.
Beyond developmental conditions, aberrant Delta-Notch signaling is also implicated in various cancers, where it can act as either an oncogene, promoting tumor growth, or a tumor suppressor, depending on the specific cell type and context. A prominent example is T-cell acute lymphoblastic leukemia (T-ALL), a blood cancer where activating mutations in the NOTCH1 receptor are found in over 50-60% of cases. These mutations lead to a continuously active Notch1 protein, which drives uncontrolled proliferation and survival of T-cells by upregulating genes like MYC and CCND3, and suppressing tumor suppressors such as PTEN.
In solid tumors, the role of Notch signaling is more complex, with mutations in Notch family members being less frequent compared to T-ALL. However, dysregulation of the pathway is still observed in various solid cancers, including breast cancer, glioblastoma multiforme, and non-small cell lung cancer. For instance, in some melanomas, Notch signaling can increase resistance to certain therapies and influence cancer cell migration. The pathway’s involvement in maintaining cancer stem cell populations in some solid tumors also makes it a focus for potential therapeutic interventions.