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The Generation and Function of Protocadherin Cell Surface Diversity in Mammalian Neural Circuit Assembly

Event Details

Friday Lecture Series
Tom Maniatis, Ph.D., Isidore S. Edelman Professor and chair, department of biochemistry and molecular biophysics, Columbia University Medical Center

The vertebrate clustered Protocadherin (Pcdh) genes, which are expressed in the nervous system, are encoded in contiguous gene clusters (α, β, γ) spanning over 1 million base pairs of DNA. The unique genomic organization of the Pcdh gene clusters, and a novel mechanism of stochastic promoter choice endows individual neurons with an extensive repertoire of Pcdh cell surface diversity. This diversity is further increased by the random dimerization of individual Pcdh isoforms, which engage in highly specific homophilic interactions as cis/trans hetero-tetramers. The unique antiparallel association of Pcdh dimers with each other revealed in structural studies affords the possibility of forming an extensive protein lattice or zipper-like interface that enhances the specificity of Pcdh interactions at the cell surface.

Functional studies in mice reveal that the clustered Pcdhs function in dendritic self-avoidance in starburst amacrine cells of the retina, and in axonal self-avoidance in olfactory sensory neurons during the formation of glomeruli. In addition, a single Pcdh isoform is required for tiling of serotonergic neurons as they project from the raphe to distribute serotonin throughout the brain. Pcdh mutations result in clumping of serotonergic neurons and depression-like behaviors. The Pcdh locus has been identified by others as one of the many loci in which DNA sequence variants associate with Autism in family studies. Thus, the clustered Pcdhs may play a fundamental role in brain wiring in humans and in neurological diseases.

Dr. Maniatis is a graduate of the University of Colorado, and received his Ph.D, from the Department of Molecular Biology at Vanderbilt University in the Laboratory of Leonard Lerman. Maniatis received postdoctoral training with Mark Ptashne at Harvard University and Fred Sanger at the MRC Cambridge England. He has held faculty positions at the Cold Spring Harbor Laboratory, the California Institute of Technology, and Harvard University prior to joining the faculty at Columbia. Maniatis is known for the development and application of recombinant DNA methods to studies of gene regulation at the levels of transcription, RNA splicing and signal transduction. He is a member of the National Academy of Science and the National Academy of Medicine, and a recipient of the Lasker-Koshland Special Achievement Award in Medical Science.

Justin Sloboda
(212) 327-7785
Open to
Luciano Marraffini, Ph.D.
Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge
Justin Sloboda
(212) 327-7785

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