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A new animal model to elucidate mechanisms of gene regulation and embryonic patterning

Award Number: R35GM147273
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: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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A new animal model to elucidate mechanisms of gene regulation and embryonic patterning - Project Summary Hox genes serve as critical regulators of developmental processes. Disruption of their function during embryogenesis results in dramatic “homeotic” phenotypes where regions of the body are transformed from one identity to another. In humans, these disruptions can lead to malformation of the face, ears, limbs, and genitalia, as well as neural defects and cancer. In many animal genomes, the Hox genes are found in clusters: in vertebrates, these clusters are compact, while those of invertebrates are more loosely arranged or fragmented. While still poorly understood, the structure of the Hox cluster is hypothesized to be important in regulating their deployment. However, this is difficult to study in vertebrates as their genomes encode multiple Hox clusters that are the result of whole genome duplications. While invertebrates typically have a single complement of Hox genes, many invertebrate Hox clusters are disrupted, including those found in the classic invertebrate model systems like flies and nematodes. To address this deficit, we have developed resources and tools for studying cephalopod molluscs (squid and octopus), including chromosome-scale genome assemblies, extensive transcriptomics, and tools for gene manipulation. Through this work, we have found that cephalopods have a single, intact, but massively expanded Hox cluster. In fact, they encode the largest Hox clusters yet described – the squid Hox cluster is two orders of magnitude larger than those found in humans. Conservation of the Hox cluster in cephalopods is particularly striking given that their genomes are otherwise highly rearranged relative to other animals. Notably, we have found that cephalopod Hox genes exhibit the canonical, collinear nested domains of expression, suggesting that elements of the ancestral regulatory program are retained in cephalopods despite the dramatic increase in cluster size. Surprisingly, our preliminary knockout data suggest that loss of a Hox gene results in the absence, rather than the transformation, of body regions. These results - the first functional analysis of Hox genes in a mollusc - point to a fundamentally different mode of action than the homeotic transformations characteristic of overtly segmented animals like flies and humans. Understanding differences between the massive cephalopod Hox clusters and the more compact arrangement found in vertebrates will provide fundamental insights concerning the regulation of these body plan transcription factors across diverse animal species, including humans. This project is therefore poised to provide transformational insights into the biology of Hox genes, which play key roles in human development and disease, and contribute to our fundamental knowledge of how pattern is established in embryogenesis.


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 = -$2,066 )
2026	2025	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	4	4/6/2026	NON-COMPETING CONTINUATION	-$350,125
2026	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	002	5	4/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	4/7/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$348,059
														Subtotal = -$2,066

Issue Date FY: 2025 ( Subtotal = $423,750 )
2025	2025	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	4	8/15/2025	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2024 ( Subtotal = $423,750 )
2024	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	3	8/15/2024	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2023 ( Subtotal = $673,750 )
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	001	2	9/18/2023	SUPPLEMENT FOR EXPANSION	$250,000
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	2	7/27/2023	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $673,750

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	1	8/26/2022	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $1,942,934

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A new animal model to elucidate mechanisms of gene regulation and embryonic patterning

Award Number: R35GM147273

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: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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