The function of single neuron protocadherin diversity in the mammalian brain
Tom Maniatis, Ph.D. Chairman, Department of Biochemistry and Molecular Biophysics - Columbia University Medical Center
Host: Ben Barres
The unique genomic organization of the clustered Pcdh proteins, and a mechanism of biallelic stochastic promotor choice, generates enormous protein diversity at the cell surface of individual mammalian neurons. This mechanism involves CTCF/cohesin-dependent DNA looping between distant transcription enhancer elements and individual Pcdh promoters. Functional Pcdh diversity is further amplified by a mechanism of combinatorial homophilic interactions between multiple Pcdhs, and a novel structure of Pcdh cis/trans tetramer complexes. Molecular genetic studies in mice have shown that the clustered Pcdhγ proteins are required for dendritic self-avoidance of starburst amacrine, and Purkinje neurons. Cell-autonomous deletion of the Pcdhα gene cluster in mice results in serotonergic wiring defects and behavioral abnormalities. Whole exome human DNA sequencing studies by others have implicated the clustered Pcdhs in autism and mental retardation. Taken together, these studies demonstrate the essential function of the clustered Pcdh proteins in normal brain wiring and function.dh proteins in normal brain wiring and function.