Notch-Delta signaling is a fundamental cell communication system found in nearly all animals, orchestrating diverse biological processes. This ancient signaling pathway allows cells to communicate directly with their neighbors. It regulates cell fate decisions, influencing cell development, multiplication, and programmed cell death. This network ensures proper tissue development and maintenance.
Understanding Notch-Delta Signaling
The Notch-Delta signaling pathway relies on direct contact between two adjacent cells. One cell, termed the “signal-sending cell,” expresses a ligand protein, typically from the Delta or Jagged families, on its surface. The neighboring cell, the “signal-receiving cell,” has a Notch receptor protein on its own surface. Mammals possess four different Notch receptors: NOTCH1, NOTCH2, NOTCH3, and NOTCH4, along with five known ligands: Delta-like (DLL1, DLL3, DLL4), Jagged1, and Jagged2.
When a Delta or Jagged ligand on one cell binds to a Notch receptor on an adjacent cell, it triggers a series of events within the receiving cell. This binding induces a conformational change in the Notch receptor, exposing a region called the Negative Regulatory Region (NRR). Following this, the Notch receptor undergoes two sequential cleavages. The first cleavage is performed by a metalloproteinase of the ADAM family, removing the extracellular part of the receptor.
The remaining membrane-tethered fragment is then cleaved a second time by an enzyme complex called gamma-secretase. This final cleavage releases the Notch Intracellular Domain (NICD) into the cytoplasm of the receiving cell. The NICD then travels to the cell’s nucleus, where it forms a complex with DNA-binding proteins and co-activators. This complex then directly activates the transcription of specific target genes, ultimately altering the cell’s behavior and fate.
Roles in Cellular Development
The Notch-Delta system plays roles in normal biological development, guiding cells to adopt appropriate identities and functions. In neurogenesis, the process of nerve cell development, Notch signaling is a key regulator of neural stem cell maintenance and differentiation. It controls the balance between quiescent (inactive) and activated states of neural stem cells and influences whether they become neurons or glial cells.
In hematopoiesis, the formation of blood cells, Notch signaling is essential for the generation of definitive embryonic hematopoietic stem cells (HSCs). While Notch1 is required for HSC generation in the embryo, its role in maintaining HSCs in adult organisms is less pronounced, differing from its continuous requirement in neuronal stem cells. Notch also influences several steps in T-cell development, guiding the commitment of multipotent hematopoietic progenitors to the T-cell lineage.
Beyond blood and nerve cells, Notch-Delta signaling is involved in the development of various organs. It plays a part in the complex processes of heart development, impacting structures like the atrioventricular canal, ventricles, and ventricular outflow tract. Kidney development is also tightly regulated by Notch signaling, with Notch2 and Jagged1 playing roles in the formation of epithelial vesicles. This widespread involvement underscores its function in ensuring cells make correct decisions about their identity and contribute to the proper formation of diverse tissues and organs.
Notch-Delta in Health and Illness
Dysregulation of the Notch-Delta signaling pathway, whether due to overactivity or underactivity, can lead to a range of health conditions and diseases. Mutations in Notch pathway components are linked to various congenital disorders. For instance, Alagille syndrome (ALGS), a multisystem disorder affecting the liver, heart, eye, skeleton, and other organs, is primarily caused by mutations in the JAG1 gene, which encodes a Notch ligand, or less commonly, in the NOTCH2 receptor gene. This leads to an incomplete development of intrahepatic bile ducts, causing symptoms like jaundice and cholestasis.
Notch signaling also has a well-documented role in different types of cancer. Aberrant activation of NOTCH1, often due to activating mutations, is observed in over 60% of T-cell acute lymphoblastic leukemia (T-ALL) cases, highlighting its contribution to the pathogenesis of this aggressive hematologic malignancy. In breast cancer, elevated levels of Notch receptors and ligands, such as Notch1, Notch4, and DLL4, are associated with cancer progression and can correlate with a poorer prognosis. The pathway’s involvement in tumor angiogenesis and cancer stem cell renewal makes it a subject of ongoing research for potential therapeutic strategies.