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Genetic control of developmental timing

Award Number: R35GM131741
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Genetic control of developmental timing - 1 Project Summary/Abstract Development of even the simplest of multicellular animals is astonishingly complex, involving the spatial and temporal orchestration of cellular proliferation, differentiation, and morphogenesis throughout the developing organism. The success of the species demands that its developmental programs are robust and resilient in the face of environmental and physiological perturbations – ‘everyday stresses’ that the developing animal’s circumstances routinely present. We study how genetic regulatory networks (GRNs) control temporal patterns of developmental events in animals, with an emphasis on understanding how microRNAs and other post-transcriptional regulators contribute to the robustness and stress resilience of animal development. We have worked primarily with the nematode Caenorhabditis elegans (C. elegans), studying a set of genes (the ‘heterochronic genes’) whose products function in a GRN that controls the timing of developmental cell fate transitions during larval development. At the core of the heterochronic GRN is the developmentally dynamic deployment of transcription factors that specify stage-specific cell fates for diverse cell types, under the control of microRNAs and RBPs that regulate the precisely timed changes in the levels of those transcription factors. C. elegans developmental timing offers an advantageous system to study developmental robustness, owing to the remarkably invariant cell lineage development of the wild type despite the free-living lifestyle of larvae, who grow up ‘in the wild’ foraging in the soil for microbial food. Consistent with roles for microRNAs in developmental robustness, the phenotypes of microRNA gene mutants are often conditional -- modifiable by environmental or physiological stresses that have no impact on wild type developmental fidelity. Our aim for the next 5 years is to advance mechanistic understanding of how microRNAs collaborate with other noncoding RNAs and RNA binding proteins (RBPs) to enable stress-robust specification of developmental cell fates. Our research plan will continue to leverage C. elegans developmental timing for discovery and characterization of how microRNAs collaborate with other regulators to enable stress-robust heterochronic GRN functionality. We also have added new elements to our research, involving the study of microRNAs in whole-body regeneration of the Acoel worm, Hofstenia miamia (H. miamia). The capacity for tissue replacement and regeneration is essentially universal across multicellular animals, presumably reflecting evolutionary roots in mechanisms of whole-body regeneration possessed by our ancient bilaterian ancestor. We view whole body regeneration as a particularly stressful context for an animal, involving as it does abrupt changes in gene expression, proliferation, and cell fate specification. We anticipate that new understanding of evolutionarily ancient functions of microRNAs in stress robustness can emerge from these H. miamia studies of whole-body regeneration.


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 = $844,267 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	004	6	5/23/2025	COMPETING CONTINUATION	$75,886
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	002	6	1/15/2025	COMPETING CONTINUATION	$844,267
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	003	5	5/23/2025	NON-COMPETING CONTINUATION	-$75,886
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	5	1/7/2025	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $844,267

Issue Date FY: 2023 ( Subtotal = $820,328 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	6/27/2023	NON-COMPETING CONTINUATION	$820,328
														Subtotal = $820,328

Issue Date FY: 2022 ( Subtotal = $820,328 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	4	4/26/2022	NON-COMPETING CONTINUATION	$820,328
														Subtotal = $820,328

Issue Date FY: 2021 ( Subtotal = $820,328 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	3	4/20/2021	NON-COMPETING CONTINUATION	$820,328
														Subtotal = $820,328

Issue Date FY: 2020 ( Subtotal = $857,178 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	2	4/21/2020	NON-COMPETING CONTINUATION	$857,178
														Subtotal = $857,178

Issue Date FY: 2019 ( Subtotal = $857,178 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	1	4/9/2019	NEW	$857,178
														Subtotal = $857,178

Grand Total All Awards = $5,019,607

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Genetic control of developmental timing

Award Number: R35GM131741

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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