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SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON DIFFERENTIATION

Award Number: R01NS041021
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2001
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON DIFFERENTIATION - The long-term goals of the proposed research are to elucidate the epigenetic mechanisms that control neuronal connectivity in the brain. We have recently discovered essential roles for the chromatin remodeling enzyme Chd4 in granule neuron connectivity in the mouse cerebellum. Strikingly, genome-wide analyses of the cerebellum in conditional Chd4 knockout mice reveal that Chd4 triggers deposition of the histone variant H2A.z at promoters of neuronal activity-dependent genes in vivo, thereby triggering their shutoff. Purification of ribosome-associated mRNAs from synchronously developing granule neurons shows that conditional knockout of Chd4 impairs shutoff of activity-dependent genes when neurons undergo dendrite pruning in vivo. Accordingly, Chd4-dependent shutoff of activity genes drives granule neuron dendrite pruning in vivo. Our findings define an epigenetic mechanism that shuts off activity-dependent transcription and thereby regulates dendrite patterning in the brain. These findings also raise fundamental questions on the regulation and mechanisms of Chd4-control of gene expression and neuronal connectivity in the brain. The ATPase Chd4 represents the core subunit of the nucleosome remodeling and deacetylase (NuRD) complex. We will elucidate the role of the protein Mbd3, which is required for the assembly of the NuRD complex, in Chd4-induced H2A.z- dependent shutoff of activity genes and granule neuron dendrite patterning in the mouse brain in vivo. We will also determine whether Chd4, like the chromatin remodeling enzyme p400, directly incorporates H2A.z into nucleosomes, and assess the role of p400 in the Chd4/H2A.z epigenetic pathway. Finally, we will characterize the biological role of the Chd4/H2A.z epigenetic pathway in granule neuron responses in the context of cerebellar circuitry. The proposed research will advance our understanding of the epigenetic mechanisms that control neuronal connectivity in the brain. Because mutations of epigenetic regulators including Chd4 cause neurodevelopmental disorders of cognition including autism and intellectual disability, our studies will also shed light on pathogenic mechanism underlying these major disorders of the brain.


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 = $0 )
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	6/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $577,776 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	3/6/2023	NON-COMPETING CONTINUATION	$577,776
														Subtotal = $577,776

Issue Date FY: 2022 ( Subtotal = $577,776 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	2/25/2022	NON-COMPETING CONTINUATION	$519,995
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	4/1/2022	NON-COMPETING CONTINUATION	$57,781
														Subtotal = $577,776

Issue Date FY: 2021 ( Subtotal = $577,776 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	2/24/2021	NON-COMPETING CONTINUATION	$577,776
														Subtotal = $577,776

Issue Date FY: 2020 ( Subtotal = $577,166 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	2/28/2020	NON-COMPETING CONTINUATION	$577,166
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	6/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $577,166

Issue Date FY: 2019 ( Subtotal = $574,109 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	2/26/2019	COMPETING CONTINUATION	$574,109
2019	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	6/7/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $574,109

Issue Date FY: 2017 ( Subtotal = $332,500 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	5/31/2017	NON-COMPETING CONTINUATION	$33,250
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/26/2017	NON-COMPETING CONTINUATION	$299,250
														Subtotal = $332,500

Issue Date FY: 2016 ( Subtotal = $332,500 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	2/2/2016	EXTENSION WITH OR WITHOUT FUNDS	$332,500
														Subtotal = $332,500

Issue Date FY: 2015 ( Subtotal = $332,500 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	1/26/2015	NON-COMPETING CONTINUATION	$332,500
														Subtotal = $332,500

Issue Date FY: 2014 ( Subtotal = $329,176 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	3/10/2014	NON-COMPETING CONTINUATION	$29,926
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/4/2014	NON-COMPETING CONTINUATION	$299,250
														Subtotal = $329,176

Issue Date FY: 2013 ( Subtotal = $332,500 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	1/18/2013	COMPETING CONTINUATION	$369,688
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	11	2/11/2013	COMPETING CONTINUATION	-$369,688
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	2/11/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$332,500
														Subtotal = $332,500

Issue Date FY: 2010 ( Subtotal = $366,612 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/9/2010	NON-COMPETING CONTINUATION	$366,612
														Subtotal = $366,612

Issue Date FY: 2009 ( Subtotal = $370,315 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/10/2009	NON-COMPETING CONTINUATION	$370,315
														Subtotal = $370,315

Issue Date FY: 2008 ( Subtotal = $370,315 )
2008	2008	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	6/18/2008	NON-COMPETING CONTINUATION	$370,315
														Subtotal = $370,315

Issue Date FY: 2007 ( Subtotal = $370,315 )
2007	2007	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/2/2007	NON-COMPETING CONTINUATION	$370,315
														Subtotal = $370,315

Issue Date FY: 2006 ( Subtotal = $381,375 )
2006	2006	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/10/2006	COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2005 ( Subtotal = $258,000 )
2005	2005	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/20/2005	NON-COMPETING CONTINUATION	$258,000
														Subtotal = $258,000

Issue Date FY: 2004 ( Subtotal = $258,000 )
2004	2004	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/17/2004	NON-COMPETING CONTINUATION	$258,000
														Subtotal = $258,000

Issue Date FY: 2003 ( Subtotal = $258,000 )
2003	2003	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/8/2003	NON-COMPETING CONTINUATION	$258,000
														Subtotal = $258,000

Issue Date FY: 2002 ( Subtotal = $258,000 )
2002	2002	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/4/2002	NON-COMPETING CONTINUATION	$258,000
														Subtotal = $258,000

Issue Date FY: 2001 ( Subtotal = $297,436 )
2001	2001	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/16/2001	NEW	$297,436
														Subtotal = $297,436

Grand Total All Awards = $7,732,147

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SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON DIFFERENTIATION

Award Number: R01NS041021

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2001

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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