The overall objective of the proposed research is to determine the mechanism by which the clustered protocadherins (Pcdhs) mediate neuronal self-avoidance, a critical property of all nervous systems. The Pcdhs, encoded in three large gene clusters controlled by alternative promoter choice, are expressed stochastically in neurons, diversifying each neuronal plasma membranes with distinctive sets of Pcdh isoforms. This diversity is thought to underlie a molecular ?barcode? for individual neurons, which allows cells to distinguish between self and non-self to mediate self-avoidance. In the prior funding period we defined the functional architecture of Pcdhs, showing that they form promiscuous cis-dimer recognition units in their membrane-proximal domains, and recognize other Pcdh recognition units in trans through large interfaces encoded in domains EC1-EC4. We mapped these interfaces by x-ray crystallography and mutagenesis. The requirement that Pcdhs encode sufficient diversity to avoid inappropriate recognition of non-self neurons as self, has led us to propose two alternative models, each in molecular detail, for Pcdh function. This proposal, is aimed at distinguishing these models to arrive at the true mechanism of Pcdh function.

Public Health Relevance

Defects in neural circuit assembly are thought to play a key role in a number of neurological disorders, ranging from autism, to mood disorders, to epilepsy. Based on recent observations linking mutations in the clustered protocadherins to autism and epilepsy, a better understanding of the structure and function of protocadherins may provide important insights into these diseases and lead to new modes of treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH114817-08
Application #
9961654
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Driscoll, Jamie
Project Start
2013-09-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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