Cadherin-4, also known as R-cadherin, is a molecule that facilitates how cells connect and communicate with each other, an interaction fundamental to the development and organization of tissues. The specific ways Cadherin-4 enables cells to adhere has significant implications for the formation of complex structures, particularly within the nervous system. Understanding its function provides insight into the processes that govern tissue architecture and stability.
What is CDH4?
The CDH4 gene provides instructions for building the protein Cadherin-4, also known as R-cadherin, with the “R” standing for retinal. Cadherin-4 is part of the cadherin superfamily, proteins that act as a biological glue to mediate cell-to-cell adhesion. A defining characteristic of this protein family is its dependence on calcium ions to function correctly; without calcium, the adhesive bond is lost.
Cadherin-4 is a transmembrane protein, meaning it passes through the cell’s outer membrane to link the inside of the cell to the outside environment. The portion of the protein extending outside the cell has five sections called extracellular cadherin repeats. These repeats bind to corresponding repeats on an adjacent cell, locking them together. Inside the cell, a cytoplasmic tail connects to other proteins, anchoring the cadherin to the cell’s internal scaffolding.
Where CDH4 is Found and Its Primary Roles
The CDH4 protein is produced in various tissues during development and in mature organs, with notable concentrations in the central nervous system. It is found in many brain regions, including the temporal lobe, amygdala, and cerebellum, as well as in the retina. Beyond the nervous system, CDH4 is also present in the kidneys, certain muscles, and various stem cells.
The main function of CDH4 is to mediate a specific type of cell adhesion known as homophilic binding. This means a Cadherin-4 protein on one cell preferentially binds to another Cadherin-4 protein on a neighboring cell. This self-recognition mechanism allows cells of the same type to sort themselves and stick together. This selective adhesion is a process for forming distinct tissues and maintaining boundaries between them.
This process of cell sorting is a component of morphogenesis, the biological process that causes an organism to develop its shape. By ensuring that cells are correctly positioned relative to one another, CDH4 contributes to the structural integrity of tissues. For instance, it helps establish the layered structure of the retina and is involved in the development of the kidney and muscle tissue.
CDH4 in Neural Development and Function
In the nervous system, Cadherin-4 performs specialized duties for building a functional brain. During early development, newly formed neurons must travel from their birthplace to their final destination. CDH4 aids this neuronal migration, acting as a guidepost that helps neurons navigate the developing brain to settle in their correct locations.
Once neurons are in position, they extend long fibers called axons to connect with other neurons and form circuits. CDH4 is involved in axon guidance, helping these fibers find their precise targets. It also promotes axon fasciculation, a process where axons traveling along similar paths bundle together like wires in a cable. This bundling creates organized and efficient nerve pathways.
The protein’s role extends to the formation and maturation of synapses, the specialized junctions where neurons communicate. By mediating adhesion at these sites, CDH4 helps stabilize these connections, allowing for the establishment of durable neural circuits. These circuits are the foundation for all brain functions, from processing sensory information to forming memories.
CDH4’s Link to Health Conditions
Alterations in the amount or function of the CDH4 protein have been linked to several human diseases. Dysregulated CDH4 is connected to various forms of cancer. In some cases, such as in certain bladder cancers, a loss of CDH4 can make cancer cells less adherent, potentially allowing them to detach from the primary tumor and spread to other parts of the body.
Conversely, in other types of cancer like triple-negative breast cancer, high levels of CDH4 expression are associated with the disease. This indicates that the role of CDH4 in cancer is complex and depends on the specific cancer type and cellular context. For example, in some scenarios, it might promote tumor growth by influencing cell signaling pathways.
Variations in the CDH4 gene are also associated with neurological and neurodegenerative conditions. Studies have identified a potential link between a genetic variant in CDH4 and Multiple System Atrophy, a rare neurodegenerative disorder. Research has shown elevated levels of CDH4 protein in affected brain regions of individuals with this condition. Ongoing investigation into these associations is clarifying how changes in this cell adhesion molecule may contribute to disease.