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The impact of loss of function DNA sequence variants in the human protocadherin gene cluster on neural circuit assembly.

Award Number: R01MH130592
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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The impact of loss of function DNA sequence variants in the human protocadherin gene cluster on neural circuit assembly. - REVISED PROJECT SUMMARY/ABSTRACT: Complex neural circuits are accurately assembled between the approximately 80 billion neurons in the human brain during development. The mammalian clustered protocadherin (Pcdh) genes, which encode a family of highly diverse cell-surface homophilic binding proteins, provide individual neurons with a unique cell-surface identity, or barcode required for normal neural circuit assembly. Previous structural, functional, and gene expression studies of the clustered Pcdh genes and proteins have revealed complex mechanisms by which Pcdh barcodes are generated and function, as well as the impact of loss of function Pcdh mutations on neural circuit assembly and behavior in mice. A remarkable feature of the Pcdh barcode is that it consists of a cell surface protein “lattice” on the membranes of interacting neurons. The Pcdh barcode has been shown to play a critical role in neurite self-avoidance, neuronal tiling and normal behavior in mice. Dominant loss of function Pcdh mutations that disrupt cell-cell interactions have been demonstrated in cell culture studies. Although the failure to accurately assemble neural circuits has been linked to neurodevelopmental and neuropsychiatric disorders, the occurrence of single nucleotide variants (SNVs) in individual PCDH genes across the PCDH gene cluster do not meet a genome wide statistical association criteria for genetic association in large scale DNA sequencing studies of autism spectrum disorder (ASD) cohorts. However, advances in understanding the regulation and function of the PCDH gene cluster and the recent availability of lymphoblastoid cell lines (LCLs) from ASD probands in the Simons Simplex cohort bearing disruptive de novo SNVs in PCDH genes presents a unique opportunity to further explore PCDH gene function in human neurons derived from human induced pluripotent stem cells. The aims are to conduct a systematic analysis of de novo SNVs across the PCDH gene clusters identified in ASD cases. In Aim 1 we will determine how SNVs in PCDH isoforms impact homophilic interactions and intracellular localization of PCDH proteins in cell-based in-vitro homophilic binding assays. In Aim 2, we will generate CRISPR-Cas9 edited hiPSCs bearing loss of function PCDH mutations and differentiate them into neurons to assess deficits in self-avoidance in the hiPSC-derived neurons. In Aim 3, we will investigate the impact of SNVs in PCDH isoforms on neural circuits and functional connectivity in mice, using serotonergic neurons as a model. These proposed studies should significantly advance our understanding of the functional role of the PCDH locus in neural circuit assembly during brain development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $810,187 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	8/22/2025	NON-COMPETING CONTINUATION	$810,187
														Subtotal = $810,187

Issue Date FY: 2024 ( Subtotal = $753,507 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	4/29/2024	NON-COMPETING CONTINUATION	$753,507
														Subtotal = $753,507

Issue Date FY: 2023 ( Subtotal = $748,572 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	6/26/2023	NEW	$748,572
														Subtotal = $748,572

Grand Total All Awards = $2,312,266

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The impact of loss of function DNA sequence variants in the human protocadherin gene cluster on neural circuit assembly.

Award Number: R01MH130592

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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