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Dissecting the role of NOTCH2NL genes in human brain development and neurological disorders associated with chromosome 1q21.1 distal duplications and deletions.

Award Number: R01MH120295
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genomic copy number variation (CNV) in a part of human chromosome 1 emerged recently in the human lineage by repeated segmental duplications and rearrangements. CNVs here have been associated with autism, schizophrenia and other neurodevelopmental disorders in multiple genome-wide association studies. However, the gene(s) in this interval that contribute to these phenotypes have not been established. We recently identified a family of 3 genes, NOTCH2NLA, -B and -C that reside in this locus, are highly expressed during early brain development and are capable of promoting cortical neuron stem cell maintenance and proliferation. In this proposal we test the hypothesis that NOTCH2NL genes are required for normal human brain development and alterations in their gene dosage contribute the neurological phenotypes observed in patients with 1q21.1 distal deletions and duplications. This will be accomplished in Aim 1 by resequencing this genomic interval in diverse human population samples using new long genomic fragment sequencing technologies that will enable us to identify the NOTCH2NL alleles present in the human population and structural variation present in this highly repetitive genomic region. This information will inform subsequent sequence analysis of 14 samples harboring pathogenic 1q21.1 CNV events that may implicate specific NOTCH2NL loci and variants in these disorders. This information will be used to develop high throughput, cost-effective assays to identify the specific NOTCH2NL alleles present in large genomic DNA collections from patients with 1q21.1-associated neurological disorders. In Aim 2, we will test the activity of the various NOTCH2NL alleles identified in 2 ways. First, examine the ability of each NOTCH2NL allele to promote NOTCH signaling using reporter based assays. Second, we will test the activity of specific NOTCH2NL alleles to promote normal cortical organoid formation using isogenic CRISPR engineered pluripotent stem cell lines that differ only by the specific NOTCH2NL alleles present. The ability of specific alleles to rescue defects in the balance of neural stem cells and cortical neurons associated with loss of NOTCH2NL will be measured by single-cell RNA Sequencing, bulk gene expression measurements and histology. Finally, in Aim 3 we will test whether heterozygous, large-scale 1q21.1 deletions similar to those observed in patients have similar or more severe defects in early brain development as assayed by our human pluripotent stem cell cerebral cortex organoid assay using the analysis methods described for Aim 2. We will then test the ability of NOTCH2NL and other genes in locus to rescue any defects observed. The experiments outlined here will improve our understanding of the specific biological defects resulting from 1q21.1 CNVs that ultimately lead to complex neurological disorders. These methods can be applied to other repetitive genomic loci implicated in neurodevelopmental diseases.


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: 2024 ( Subtotal = $726,976 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	001	5	8/14/2024	NON-COMPETING CONTINUATION	$72,697
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	5	1/30/2024	NON-COMPETING CONTINUATION	$654,279
														Subtotal = $726,976

Issue Date FY: 2023 ( Subtotal = $726,976 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	4	1/13/2023	NON-COMPETING CONTINUATION	$726,976
														Subtotal = $726,976

Issue Date FY: 2022 ( Subtotal = $726,976 )
2022	2022	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	001	3	5/23/2022	NON-COMPETING CONTINUATION	$72,697
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	3	1/14/2022	NON-COMPETING CONTINUATION	$654,279
														Subtotal = $726,976

Issue Date FY: 2021 ( Subtotal = $726,976 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	2	1/25/2021	NON-COMPETING CONTINUATION	$726,976
														Subtotal = $726,976

Issue Date FY: 2020 ( Subtotal = $762,904 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	1	4/8/2020	NEW	$762,904
														Subtotal = $762,904

Grand Total All Awards = $3,670,808

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Dissecting the role of NOTCH2NL genes in human brain development and neurological disorders associated with chromosome 1q21.1 distal duplications and deletions.

Award Number: R01MH120295

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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