Protocadherine

Protocadherins are a subfamily of the cadherin-related cell adhesion molecules, members of the larger cadherin superfamily. They are expressed predominantly in the vertebrate nervous system and play an important role in establishing neuronal identity and synaptic specificity. The protocadherin gene family is large and highly diverse, enabling a combinatorial code that contributes to wiring of neural circuits.

In humans, clustered protocadherins are organized into three gene clusters: PCDHA, PCDHB, and PCDHG, located on chromosome 5q31. Each cluster contains numerous variable exons that encode the extracellular cadherin repeats and the transmembrane region, which are spliced to shared constant exons encoding the cytoplasmic tail. This architecture creates a large repertoire of isoforms from alternative promoter usage, allowing individual neurons to express a unique set of protocadherin proteins on their surface.

Structurally, protocadherins are single-pass transmembrane proteins with extracellular regions containing multiple cadherin repeats (EC domains) and a cytoplasmic tail that participates in intracellular signaling. They can engage in cis interactions on the same cell surface and trans interactions with protocadherins on neighboring cells, contributing to cell–cell recognition and adhesion.

Functionally, protocadherins contribute to neural development by guiding neurite outgrowth, dendritic arborization, and synapse formation. Their stochastic and combinatorial expression patterns create a molecular mosaic that supports self-avoidance and precise synaptic wiring.

Clinical and evolutionary notes: Alterations in protocadherin expression or gene regulation have been linked to neurodevelopmental disorders in some studies, and several protocadherin family members are implicated as tumor suppressors in certain cancers. The protocadherin family reflects a vertebrate innovation that underpins neuronal diversity.