Protocadherins (PCDH) represent a large and diverse family of proteins that play important roles in the biological processes of vertebrates. While lesser known than some other molecular families, their presence across a wide range of species suggests a deep evolutionary history. These proteins are particularly important in the brain, where they contribute to the precise organization and function of neural circuits. Understanding protocadherins provides insight into brain development and overall biological function.
Understanding Protocadherins
Protocadherins are a major subgroup within the cadherin superfamily of cell adhesion molecules. They are primarily found on the surface of neuronal cells, acting as transmembrane proteins. A distinguishing feature of protocadherins is their classification into two main types: clustered and non-clustered. Clustered protocadherins are organized into three gene clusters, designated alpha (α), beta (β), and gamma (γ), on the same chromosome in mammals. Non-clustered protocadherins, in contrast, are scattered throughout the genome.
These proteins possess a unique structure that sets them apart from classical cadherins. Their extracellular domain is longer and features six cadherin-like ectodomain repeats. Unlike classical cadherins, protocadherins lack the typical interface for strong homophilic adhesiveness and do not directly attach to the cytoskeleton through catenins in their intracellular domain. The diversity of protocadherins, with approximately 70 genes identified in mammalian genomes, arises from their unique genetic organization. Over 50 of these genes are located in tightly linked gene clusters, where each variable exon is transcribed from its own promoter, leading to a vast array of cell surface identities.
Orchestrating Brain Development
Protocadherins are involved in shaping the developing brain. They contribute to neuronal self-avoidance, a mechanism where branches from a single neuron repel each other. This self-recognition allows neurons to avoid tangles and ensures efficient coverage of their receptive fields, preventing inappropriate self-connections. This is achieved through isoform-specific homophilic interactions, where identical protocadherin isoforms on the same neuron recognize and interact.
The diverse array of protocadherin isoforms provides each neuron with a unique identity code. This allows a neuron to distinguish its own processes from those of neighboring neurons, enabling self/non-self discrimination. For example, the gamma-protocadherin (Pcdhg) cluster, comprising 22 genes in mice, is directly involved in mediating self-avoidance. When all Pcdhg genes are deleted, self-avoidance is disrupted, but it can be restored by introducing a single isoform.
Beyond self-avoidance, protocadherins also participate in cell-cell adhesion, guiding neuronal migration, and facilitating synapse formation. Specific protocadherins, such as Pcdh10, are detected along axon fibers, suggesting their involvement in axon development and function. For instance, the knockout of Pcdh10 in mice results in defects in the formation of various axon tracts, including the thalamocortical and corticospinal tracts. These functions collectively contribute to the precise assembly of neural circuits and the overall architecture of the brain.
Links to Neurological Conditions
Dysfunction in protocadherins has been linked to various neurological and neurodevelopmental disorders. Mutations or dysregulation of protocadherin genes can disrupt neural circuit formation and synaptic function. These impairments can manifest in conditions such as autism spectrum disorder (ASD), schizophrenia, epilepsy, and Tourette’s syndrome.
In autism spectrum disorder, clustered protocadherins are candidate genes, with mutations and single nucleotide variants identified in individuals with ASD. Abnormalities in neural circuit wiring, such as altered dendritic spine density and impaired synaptic elimination, have been observed in animal models with protocadherin dysfunction. For example, Pcdh10-deficient mice exhibit social abnormalities and increased dendritic spine density in the amygdala, a brain region involved in social behaviors.
Mutations in the delta family of non-clustered protocadherins are associated with autism, intellectual disability, and epilepsy. Pcdh17 has been implicated in schizophrenia and language delay. These findings suggest that impaired protocadherin function can lead to abnormal neural circuit formation and altered synaptic connections, contributing to the complex symptoms seen in these neurodevelopmental conditions.