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Morphogen control of organ growth in Drosophila

Award Number: R35GM127141
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Morphogen control of organ growth in Drosophila - PROJECT SUMMARY The main goal of this project is to determine how morphogens control organ growth. During development, each body part grows to full size and differentiates complex cell patterns under the control of morphogens, secreted signaling molecules that spread through developing tissues and organize gene expression, pattern and growth. The major superfamilies of morphogens are conserved in all multicellular animals, from sponges to man. Understanding how they work has enormous implications for human health, as genetic and environmental perturbations of their activities and signal transduction pathways cause diverse developmental and physiological disorders as well as a wide range of cancers. Research on morphogens is thus critical for developing diagnostic and therapeutic tools to treat human disease, a central mission of the NIH. Our past studies, using Drosophila, established that members of two superfamilies of secreted proteins, Bone Morphogenetic Proteins (BMPs) and Wingless/Ints (Wnts) function as bona fide morphogens. Initially we focused on the logic and molecular mechanisms by which these molecules control gene expression and patterning. Here we turn to the fundamental and enduring mystery of how they control growth. In the proposed research, we will fill three key gaps in understanding. First, we will consolidate and extend a new “feed-forward” model for growth based on our recent discoveries unifying the roles of Decapentaplegic (Dpp, a BMP) and Wingless (Wg) in the developing Drosophila wing, a classic paradigm for morphogen action. In this model, Wg and Dpp act together to induce and sustain expression of the selector gene, vestigial (vg), which encodes a transcription factor that “selects” the wing state and programs wing cells to grow in response to Wg and Dpp. We identified a single enhancer element in the vg gene that integrates Dpp and Wg input, as well as a “recruitment” signal, the protocadherin Fat. We will now combine genetic, transgenic and molecular approaches to determine how this integration occurs and to identify downstream effectors that govern wing growth in response to Dpp and Wg. We will also test a key axiom of the model—that Dpp and Wg are required continuously, at long-range, to sustain growth—and determine how these molecules move through tissue. Second, we will apply the approaches and principles that have emerged from our analysis of the fly wing to elucidate how Dpp and Wg control the growth of other organs. We will focus on the fly leg in which Dpp and Wg as well as their downstream selector genes and signaling molecules are deployed in a manner that is highly conserved throughout the animal kingdom, but distinct from the wing. Our analysis will build on our preliminary evidence that leg growth is governed by the ranges of Dpp and Wg—as in the wing—but by different regulatory circuits and logic. Third, we will determine the role of receptor dimerization or higher order oligomerization in Wg reception by Frizzled (Fz) family GPCRs based on our discovery of unexpected functional complementation between three of the four Drosophila Fz proteins. This analysis should provide insight into how Wnts are transduced by the ten Fz proteins in humans.


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 = $678,722 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	9	4/17/2026	NON-COMPETING CONTINUATION	$678,722
														Subtotal = $678,722

Issue Date FY: 2025 ( Subtotal = $678,722 )
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	Biomedical Research and Research Training	002	8	7/15/2025	NON-COMPETING CONTINUATION	$678,722
2025	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	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	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	Biomedical Research and Research Training	001	7	6/25/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $678,722

Issue Date FY: 2024 ( Subtotal = $1,034,015 )
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	Biomedical Research and Research Training	003	7	4/10/2024	NON-COMPETING CONTINUATION	$610,849
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	Biomedical Research and Research Training	006	7	8/6/2024	SUPPLEMENT FOR EXPANSION	$250,000
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	Biomedical Research and Research Training	005	7	6/28/2024	NON-COMPETING CONTINUATION	$67,873
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	Biomedical Research and Research Training	004	7	5/7/2024	SUPPLEMENT FOR EXPANSION	$105,293
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	002	6	4/4/2024	COMPETING CONTINUATION	$34
2024	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	5	4/4/2024	SUPPLEMENT FOR EXPANSION	-$4
2024	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	5	4/4/2024	NON-COMPETING CONTINUATION	-$30
														Subtotal = $1,034,015

Issue Date FY: 2023 ( Subtotal = $678,722 )
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	Biomedical Research and Research Training	000	6	4/21/2023	COMPETING CONTINUATION	$678,722
														Subtotal = $678,722

Issue Date FY: 2022 ( Subtotal = $695,716 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	5	5/2/2022	SUPPLEMENT FOR EXPANSION	$88,073
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	5	4/29/2022	NON-COMPETING CONTINUATION	$607,643
														Subtotal = $695,716

Issue Date FY: 2021 ( Subtotal = $666,358 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	4	4/8/2021	NON-COMPETING CONTINUATION	$607,643
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	4	8/18/2021	SUPPLEMENT FOR EXPANSION	$58,715
														Subtotal = $666,358

Issue Date FY: 2020 ( Subtotal = $607,643 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	3	5/1/2020	NON-COMPETING CONTINUATION	$607,643
														Subtotal = $607,643

Issue Date FY: 2019 ( Subtotal = $607,643 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	2	4/29/2019	NON-COMPETING CONTINUATION	$607,643
														Subtotal = $607,643

Issue Date FY: 2018 ( Subtotal = $535,317 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	1	9/21/2018	SUPPLEMENT FOR EXPANSION	$50,000
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	1	4/17/2018	NEW	$485,317
														Subtotal = $535,317

Grand Total All Awards = $6,182,858

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Morphogen control of organ growth in Drosophila

Award Number: R35GM127141

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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