Historical Overview Of CadherinsEdit
Cadherins are a family of calcium-dependent cell–cell adhesion molecules that have shaped the architecture of tissues and the course of development for decades. They mediate homophilic binding between neighboring cells, help organize tissues into coherent layers, and participate in signaling pathways that influence cell fate, movement, and growth. The historical arc of cadherins runs from the first demonstrations of calcium-dependent adhesion to the molecular dissection of adhesion complexes and the diversification of cadherin genes across animals. This article traces those milestones, the key structural and functional themes, and the enduring debates that have accompanied the growth of knowledge in this area.
Historically, the discovery and characterization of cadherins unfolded through a sequence of pivotal experiments and then a rapid expansion of molecular detail. In the late 1960s and 1970s, pioneering work showed that cell–cell adhesion could be disrupted by removing calcium from the extracellular milieu, a finding that highlighted a specific, extracellularly mediated adhesion mechanism. This calcium dependence was later attributed to the cadherin family, a term that captures the essence of calcium-dependent adhesion and the proteins that execute it. The work of Masatoshi Takeichi and colleagues was especially influential in establishing that cell sorting and tissue cohesion could be explained, at least in part, by cadherin-mediated adhesion. The concept that adhesive strength was encoded at the cell surface and could be modulated by the expression pattern of cadherins helped explain how tissues maintain distinct boundaries during development. The early cadherins also revealed connections to the cytoskeleton through adapter proteins, linking adhesion to mechanical stability and signaling.
The molecular cloning era, beginning in the 1980s and accelerating in the 1990s, brought cadherins from a phenomenological concept to a gene family with defined members and domains. The best-known member, often referred to as E-cadherin, served as a paradigm for epithelial adhesion, while other members such as N-cadherin demonstrated that distinct tissues use different cadherin repertoires to achieve tissue-specific cohesion and patterning. The identification of the cadherin intracellular partners—most notably the catenins—revealed a coherent complex at the cytoplasmic face of the cadherin, connecting the adhesive interface to the actin cytoskeleton and to signaling networks. The cadherin–catenin complex thus became a central theme in understanding how physical cell–cell contacts could influence cellular behavior beyond mere sticking.
As the cadherin field matured, researchers delineated the architecture of the cadherin superfamily and how different classes contribute to tissue integrity. Classical cadherins, including Type I and Type II cadherins, mediate strong, calcium-dependent homophilic adhesion that is essential for epithelial and endothelial organization. Desmosomal cadherins, such as desmogleins and desmocollins, provide robust adhesion in tissues subjected to mechanical stress by forming desmosomes, specialized junctions that reinforce cell–cell contact. Protocadherins and other non-classical cadherins expanded the family into more nuanced roles, particularly in the nervous system, where diverse cis- and trans-interactions may contribute to the wiring of neural circuits and self-avoidance. Across evolution, cadherins show an expansion and specialization that mirror the increasing complexity of multicellular organisms, with vertebrates exhibiting pronounced diversification that supports tissue layering, organ formation, and organ-level mechanics.
The structural and mechanistic properties of cadherins are central to their historical importance. Each cadherin typically features extracellular cadherin repeats that engage in calcium-binding–dependent conformations, a single transmembrane region, and a cytoplasmic tail that interfaces with a set of anchoring proteins. The extracellular domains are responsible for homophilic binding—cadherins on neighboring cells prefer to bind to identical cadherins on adjacent cells—while the cytoplasmic side links to the actin cytoskeleton via the cadherin–catenin complex. This arrangement enables both stable adhesion and dynamic remodeling, as tissue boundaries shift during development or respond to mechanical cues. Key components include β-catenin and α-catenin, which connect cadherins to actin, and other regulators like p120 catenin that modulate cadherin stability at the cell surface. The discovery of these linkages spurred a broader view of cell–cell junctions as signal-translation hubs, not merely glue.
The historical narrative of cadherins is inseparable from their roles in development, tissue homeostasis, and disease. In development, cadherins help coordinate processes such as gastrulation, neurulation, and organogenesis by regulating cell sorting, tissue separation, and collective cell movements. In adults, they contribute to the maintenance of barriers and the integrity of epithelia and endothelia, as well as to tissue repair and remodeling. In disease, cadherins are frequently implicated in cancer biology, where shifts in cadherin expression—often characterized as a “cadherin switch” from epithelial to more motile adhesive states—are associated with changes in invasion and metastasis potential. Yet the precise contributions of cadherin loss, replacement by other cadherins, or altered signaling through cadherin-associated complexes are context-dependent, with ongoing debate and refinement in the literature. The interplay between cadherin function and signaling pathways such as the Wnt pathway, in which β-catenin also serves as a transcriptional co-activator, has been a particular focus of discussion, illustrating how adhesion molecules can influence cell fate beyond mechanical cohesion.
Controversies and debates have persisted alongside the advances. A recurring topic is the extent to which changes in cadherin expression are drivers of disease progression versus marks of cellular state. For example, while loss of a major cadherin can be consistent with reduced intercellular adhesion and increased migratory capacity, functional outcomes depend on tissue context, compensatory expression of related cadherins, and the broader signaling milieu. Similarly, the precise contributions of cadherin signaling to processes such as epithelial–mesenchymal transition (EMT) remain nuanced: EMT is a program with multiple molecular branches, and cadherins are one component among many that shape cell behavior and tissue remodeling. In the nervous system, protocadherins contribute to neural specificity and circuit formation, but their exact rules of engagement and functional redundancy are still being delineated. Across all these areas, the field emphasizes context dependency, redundancy, and the integration of adhesion with mechanical and signaling inputs.
From a historical perspective, the cadherin story demonstrates how a relatively simple biochemical constraint—calcium-dependent binding—gave rise to a sprawling family of proteins central to tissue architecture and organismal form. It also illustrates how molecular biology, structural biology, and developmental biology converged to turn an adhesion phenomenon into a framework for understanding form, function, and disease.
See also