N-cadherin is a protein in the cadherin superfamily that acts as a cellular adhesive, helping to build and maintain tissues by facilitating connections between cells. This molecule’s function is dependent on calcium, and it is found in various tissues throughout the body, where it contributes to their structural integrity and organization.
The Fundamental Role in Cell Adhesion
N-cadherin, or neural cadherin, physically links adjacent cells together. For these adhesive properties to activate, calcium ions must bind to the extracellular domains of the cadherin molecules. This stabilizes them and permits them to interact with N-cadherin on neighboring cells, creating a strong, physical bond that allows cells to function as a cohesive unit.
In the nervous system, N-cadherin is concentrated at synapses, the junctions where neurons transmit signals. At these sites, the protein helps hold the pre-synaptic and post-synaptic membranes in close proximity. This stability ensures that the intricate wiring of the nervous system remains intact, allowing for reliable communication between nerve cells.
The cardiovascular system also relies on N-cadherin. Cardiac muscle cells are joined by complex structures called intercalated discs, and N-cadherin is a component of these junctions. This structural linkage ensures that the mechanical force from one contracting cell is effectively transferred to the next, allowing the heart muscle to beat in a synchronized wave.
The intracellular portion of N-cadherin connects to the cell’s internal scaffolding, the actin cytoskeleton, through proteins called catenins. This linkage allows for the transmission of mechanical forces and signals from the cell’s exterior to its interior. This integrated network influences cell behavior and helps maintain the architectural integrity of tissues under physical stress.
Critical Functions in Development
During embryonic development, N-cadherin orchestrates the large-scale movements and reorganizations of cells that shape the growing organism. Its expression is precisely controlled, appearing at specific times and places to guide the formation of tissues. The protein’s ability to mediate selective adhesion allows cells of the same type to recognize and stick to each other, driving their sorting into distinct layers.
During neurulation, the process that forms the central nervous system, N-cadherin expression increases in the cells of the neural plate as it bends. A flat sheet of cells called the neural plate must fold and fuse to create the neural tube, the precursor to the brain and spinal cord. N-cadherin acts like a zipper to correctly align and seal the edges of the fold, ensuring the tube closes properly.
In the formation of the heart, N-cadherin is expressed by early cardiac progenitor cells. It helps these cells aggregate and organize into the primitive heart tube, which later develops into the four-chambered heart. Without it, mouse embryos develop severe heart defects and do not survive, highlighting its importance in organ construction.
N-cadherin is also involved in the migration of neural crest cells. These are a temporary group of embryonic cells that travel long distances to give rise to a variety of cell types, including neurons and facial cartilage. N-cadherin helps these cells migrate collectively as a cohesive group, maintaining cell-to-cell contacts while still allowing for movement.
The Connection to Cancer Progression
In cancer, N-cadherin is often associated with increased tumor aggressiveness and the spread of cancer cells to distant sites, a process known as metastasis. Many cancers originate in epithelial tissues, where cells are normally held in place by E-cadherin. This molecule acts as a suppressor of tumor invasion by maintaining strong cell-to-cell adhesion.
Some cancer cells undergo a change known as the Epithelial-to-Mesenchymal Transition (EMT), where they downregulate E-cadherin and begin to express N-cadherin instead. This event, called the “cadherin switch,” alters the adhesive properties of the cells. The bonds formed by N-cadherin are weaker than those of E-cadherin, allowing cancer cells to detach from the primary tumor.
The switch to N-cadherin expression actively promotes a migratory and invasive phenotype. Cells that have undergone EMT become more mobile and are better equipped to navigate through surrounding tissue and enter blood or lymphatic vessels. This enhanced motility is a direct consequence of the signaling pathways activated by N-cadherin.
Once in circulation, N-cadherin can facilitate the adhesion of cancer cells to the endothelial lining of blood vessels in distant organs, a step in forming a new tumor. The presence of N-cadherin in tumors where it is not normally found is often a marker of poor prognosis.
Involvement in Tissue Repair and Regeneration
Following an injury, N-cadherin participates in the repair process. When tissues like skin or muscle are wounded, cells near the injury must become mobile to close the gap and rebuild the damaged structure. This response involves a temporary change in cell behavior that mirrors some aspects of developmental processes.
In response to injury signals, cells at the edge of a wound increase their expression of N-cadherin. This change promotes their migration into the wound bed, where they deposit new extracellular matrix and form a scaffold for reconstruction. Once the wound is closed and the tissue is restored, N-cadherin expression levels return to normal.
This controlled use of N-cadherin to enable cell migration for repair stands in contrast to its dysregulation in cancer. In healing, its expression is temporary to facilitate necessary movement. In cancer, its sustained expression contributes to disease progression.