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Dissecting the genetic underpinnings of heterochrony in limb bud initiation

Award Number: R01HD032443
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/1995
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Dissecting the genetic underpinnings of heterochrony in limb bud initiation - ABSTRACT The overarching goal of this project is to understand how timing is controlled during embryonic development and to identify the molecular changes that led to changes in timing, or heterochrony, through evolution. In particular, we will focus on the control of the time when the limb buds start to form in the embryo. The relative timing of initiation of the fore and hind limb buds differs dramatically between birds (2-hour differential in chicks) and mammals (18-hour difference in mice). In simplest terms, the hind limb forms at a relatively later time in mice. We will attempt to understand this heterochrony on two levels: Aim 1 will address the cis-regulatory landscape regulating timing of gene activity driving limb bud initiation. Tbx4 is a transcription factor required for limb bud initiation, whose timing of expression closely matches the time at which the hind limb starts to form in both chick and mouse. Using regulation of Tbx4 as a starting point, putative enhancers have been identified in preliminary experiments that appear to drive proper temporal expression of this gene in mouse and chick. Enhancer swap experiments between these species will validate the contribution of these putative activating enhancers to timing of Tbx4 expression in the forming limbs. In parallel, we will map potential inhibitory cis-regulatory sequences at the Tbx4 locus using a “silence reporter” assay, and through loss of function experiments in mice. In a complementary set of experiments, Aim 2 will focus on identifying transcription factors mediating the relative delay in hindlimb initiation in mice. A list of candidate factors will be assembled from a comparative analysis of scRNA-Seq data on cells taken from mouse and chick fore and hind limb domains, just prior to and just after limb bud initiation. Candidates will be tested functionally through electroporation in developing chick limb field. cRel, a candidate identified in preliminary studies, will be further tested functionally in the mouse. As noted above, the timing of Tbx4 expression correlates well with the timing of hind limb bud initiation in both chick and mouse. Moreover, preliminary data suggest that at least part of the timing of this gene’s activity is established through regulation by the NFKB family member cRel. Interestingly, NFKB activity is regulated by oxygen levels in other settings, and our preliminary data indicates that this is the case for cRel in the limb bud. Accordingly, Aim 3 will dissect the regulatory relationship between oxygen levels and Tbx4 expression in the limb bud. Together, the proposed studies will break new ground towards understanding the important, but under- studied problem of timing during development, and the timing of limb bud initiation in particular.


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: 2026 ( Subtotal = $399,831 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	27	12/10/2025	NON-COMPETING CONTINUATION	$399,831
														Subtotal = $399,831

Issue Date FY: 2025 ( Subtotal = $450,712 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	26	2/24/2025	COMPETING CONTINUATION	$450,712
														Subtotal = $450,712

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	25	7/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $407,213 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	25	5/25/2021	NON-COMPETING CONTINUATION	$407,213
														Subtotal = $407,213

Issue Date FY: 2020 ( Subtotal = $415,524 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	24	6/1/2020	NON-COMPETING CONTINUATION	$415,524
														Subtotal = $415,524

Issue Date FY: 2019 ( Subtotal = $415,524 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	23	5/31/2019	NON-COMPETING CONTINUATION	$415,524
														Subtotal = $415,524

Issue Date FY: 2018 ( Subtotal = $415,524 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	22	5/30/2018	NON-COMPETING CONTINUATION	$415,524
														Subtotal = $415,524

Issue Date FY: 2017 ( Subtotal = $415,524 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	21	8/22/2017	COMPETING CONTINUATION	$415,524
														Subtotal = $415,524

Issue Date FY: 2004 ( Subtotal = $354,313 )
2004	2004	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	10	3/18/2004	NON-COMPETING CONTINUATION	$354,313
														Subtotal = $354,313

Issue Date FY: 2003 ( Subtotal = $343,995 )
2003	2003	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	9		NON-COMPETING CONTINUATION	$343,995
														Subtotal = $343,995

Issue Date FY: 2002 ( Subtotal = $330,914 )
2002	2002	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	8	3/1/2002	NON-COMPETING CONTINUATION	$330,914
														Subtotal = $330,914

Issue Date FY: 2001 ( Subtotal = $324,249 )
2001	2001	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	7	3/30/2001	NON-COMPETING CONTINUATION	$324,249
														Subtotal = $324,249

Issue Date FY: 2000 ( Subtotal = $314,803 )
2000	2000	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	6	3/24/2000	COMPETING CONTINUATION	$314,803
														Subtotal = $314,803

Issue Date FY: 1999 ( Subtotal = $258,538 )
1999	1999	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	5	3/18/1999	NON-COMPETING CONTINUATION	$258,538
														Subtotal = $258,538

Issue Date FY: 1998 ( Subtotal = $248,595 )
1998	1998	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Child Health and Human Development Extramural Research	000	4	3/17/1998	NON-COMPETING CONTINUATION	$248,595
														Subtotal = $248,595

Grand Total All Awards = $5,095,259

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Dissecting the genetic underpinnings of heterochrony in limb bud initiation

Award Number: R01HD032443

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/1995

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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