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Molecular Analysis of Hindbrain Development

Award Number: R01NS038183
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: 12/03/1998
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Molecular Analysis of Hindbrain Development - SUMMARY The extraordinary functional range of the mature CNS requires synchronized activity of neural circuits. Formation of such circuits involves the timely specification and correct positioning of neural progenitors, and disruptions to this process are associated with neurodevelopmental disorders. Hence, a key goal of developmental neurobiology is to understand the control of neural progenitor specification in space and time in embryogenesis. One mechanism for proper spatiotemporal formation of neural progenitors involves morphogen gradients that specify distinct progenitor types at different positions. While we know that morphogens do induce different progenitor types at different positions, we do not understand how individual cells interpret morphogen signals, nor how they convert this information into distinct cell identities. An informative example of CNS morphogen action is the developing hindbrain, where retinoic acid (RA) and fibroblast growth factor (Fgf) control formation of neural compartments (rhombomeres) – each of which represents a unique progenitor population. However, we do not understand the distinct genetic programs that define individual rhombomeres, nor how they arise from the earlier hindbrain primordium. Filling these knowledge gaps is essential, but a profound barrier has been the lack of comprehensive molecular data for individual progenitors as they undergo specification in response to morphogen signals. We overcame this barrier by applying scMultiome analysis – which combines RNAseq and ATACseq of individual nuclei – to several stages of hindbrain development. At the earliest stage, we detect three populations (a.k.a., PHPDs) containing progenitors with mixed rhombomere (r) identities representing r2/r3, r4 and r5/r6 and we find that these PHPDs form in response to RA and Fgf. At later stages, our analyses – for the first time – molecularly resolve all rhombomeres and define their unique gene regulatory networks (GRNs). These advances now allow us to address several key questions: How do progenitor cells respond to morphogens? How are the mixed progenitor identities resolved into individual rhombomere identities? How are unique GRNs formed in each developing rhombomere? We will answer these questions in the context of our hypothesis that morphogens act via specific cis-regulatory elements to induce mixed identity GRNs in the PHPDs, and these are subsequently resolved via repressive genetic interactions into rhombomere-specific GRNs that specify unique progenitor types. Our project will delineate how morphogens control genetic programs for positioning and specification of neural progenitors in the hindbrain. Since morphogens control neural specification throughout the developing CNS, our findings will be broadly applicable to normal brain development, to modeling of neurodevelopmental disorders, and to the implementation of restorative or replacement strategies as clinical treatments.


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 = $414,185 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	11/29/2024	NON-COMPETING CONTINUATION	$414,185
2025	2024	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	24	2/19/2025	COMPETING CONTINUATION	$13,206
2025	2022	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	23	2/19/2025	NON-COMPETING CONTINUATION	-$13,206
														Subtotal = $414,185

Issue Date FY: 2024 ( Subtotal = $460,205 )
2024	2024	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	1/9/2024	COMPETING CONTINUATION	$460,205
														Subtotal = $460,205

Issue Date FY: 2022 ( Subtotal = $369,767 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	23	3/29/2022	NON-COMPETING CONTINUATION	$36,975
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	11/8/2021	NON-COMPETING CONTINUATION	$332,792
														Subtotal = $369,767

Issue Date FY: 2021 ( Subtotal = $369,767 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	10/30/2020	NON-COMPETING CONTINUATION	$332,792
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	2/4/2021	NON-COMPETING CONTINUATION	$36,975
														Subtotal = $369,767

Issue Date FY: 2020 ( Subtotal = $369,767 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	21	1/14/2020	NON-COMPETING CONTINUATION	$12,918
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	21	2/10/2020	NON-COMPETING CONTINUATION	$36,975
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	12/6/2019	NON-COMPETING CONTINUATION	$332,792
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	21	5/8/2020	NON-COMPETING CONTINUATION	$0
2020	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	1/14/2020	NON-COMPETING CONTINUATION	-$12,918
														Subtotal = $369,767

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	9/14/2019	NON-COMPETING CONTINUATION	-$75,450
2019	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	9/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$75,450
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $398,555 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	7/26/2018	NON-COMPETING CONTINUATION	$398,555
														Subtotal = $398,555

Issue Date FY: 2017 ( Subtotal = $406,805 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	9/22/2017	COMPETING CONTINUATION	$406,805
2017	2016	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	9/22/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $406,805

Issue Date FY: 2016 ( Subtotal = $359,844 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	6/3/2016	EXTENSION WITH OR WITHOUT FUNDS	$359,844
														Subtotal = $359,844

Issue Date FY: 2015 ( Subtotal = $359,844 )
2015	2015	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	5/17/2015	NON-COMPETING CONTINUATION	$359,844
														Subtotal = $359,844

Issue Date FY: 2014 ( Subtotal = $356,246 )
2014	2014	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	5/20/2014	NON-COMPETING CONTINUATION	$356,246
														Subtotal = $356,246

Issue Date FY: 2013 ( Subtotal = $347,250 )
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	5/24/2013	NON-COMPETING CONTINUATION	$347,250
														Subtotal = $347,250

Issue Date FY: 2012 ( Subtotal = $359,844 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	4/20/2012	COMPETING CONTINUATION	$359,844
														Subtotal = $359,844

Issue Date FY: 2011 ( Subtotal = $348,359 )
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	6/24/2011	NON-COMPETING CONTINUATION	$348,359
														Subtotal = $348,359

Issue Date FY: 2010 ( Subtotal = $351,915 )
2010	2010	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	5/25/2010	NON-COMPETING CONTINUATION	$351,915
														Subtotal = $351,915

Issue Date FY: 2009 ( Subtotal = $355,469 )
2009	2009	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/3/2009	NON-COMPETING CONTINUATION	$355,469
														Subtotal = $355,469

Issue Date FY: 2008 ( Subtotal = $355,469 )
2008	2008	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/4/2008	COMPETING CONTINUATION	$355,469
														Subtotal = $355,469

Issue Date FY: 2006 ( Subtotal = $295,001 )
2006	2006	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/5/2006	NON-COMPETING CONTINUATION	$295,001
														Subtotal = $295,001

Issue Date FY: 2005 ( Subtotal = $302,100 )
2005	2005	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/24/2005	NON-COMPETING CONTINUATION	$302,100
														Subtotal = $302,100

Issue Date FY: 2004 ( Subtotal = $302,100 )
2004	2004	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	2/26/2004	NON-COMPETING CONTINUATION	$302,100
														Subtotal = $302,100

Grand Total All Awards = $8,018,102

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Molecular Analysis of Hindbrain Development

Award Number: R01NS038183

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: 12/03/1998

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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