The human protocadherin (PCDH) gene clusters (PCDH-alpha, -beta and -gamma) encode a family of cell surface proteins that function in cell-to-cell interaction during the development of the brain. Distinct subsets of PCDH genes from all three clusters are randomly expressed in individual neurons, and this results in the generation of enormous single-cell PCDH diversity in neurons that are otherwise identical.
This diversity is displayed on the surface of neurons, and if processes from the same neuron come into contact, identical sets of PCDHs on the opposing surfaces bind to each other. This interaction initiates a process called ‘self-avoidance’ whereby processes from the same neurons do not cross each other. This mechanism of neuron self-recognition plays a key role in neural circuit assembly during development.
Tom Maniatis and his colleagues at Columbia University Medical Center investigated the possibility that one of the gene clusters (PCDH-alpha) plays a role in the etiology of autism by controlling the distribution of processes from neurons that release the neurotransmitter serotonin. They compared the effects of deleting the entire PCDH-alpha gene cluster in all neurons of the mouse brain with deleting it only in serotonergic neurons.
They found that mice bearing either type of deletion display identical defects in serotonergic projections, and in affective functions — anxiety and depression. Both the wiring and behavioral defects are cell-autonomous; they are caused by the loss of PCDH-alpha genes in serotonergic neurons and not in other brain regions.
The researchers also found that mice that have had an entire PCDH-alpha gene cluster deleted in all neurons develop self-inflicted skin lesions that resemble those found in several autism models. In contrast to the other phenotypes, the researchers did not observe these lesions in mice lacking the PCDH-alpha cluster only in serotonergic neurons.
Maniatis and his group conclude that the skin lesions result from the loss of PCDH-alpha in other neuronal cell types. To address potential functional compensation between clusters, the Maniatis lab recently produced mutant mice lacking all clustered PCDHs.