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Mechanisms underpinning meiotic spindle formation and behavior

Award Number: R35GM142537
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Mechanisms underpinning meiotic spindle formation and behavior - Project summary Meiosis is a specialized form of cell division that produces haploid gametes. In oocytes, proper spindle formation and positioning within the oocyte must be tightly regulated to ensure faithful chromosome segregation and accurate genome inheritance. In somatic mitotic cells, bipolar spindle assembly and positioning rely on a pair of centrosomes, each containing two centrioles. Interestingly, meiotic oocytes lack centrioles and, hence, lack classic centrosomes. Instead, they contain numerous microtubule (MT) organizing centers (MTOCs) that are organized, by largely unknown mechanisms, to establish two spindle poles (polar MTOCs). The traditional view was that, in mammalian oocytes, MTs (and their associated proteins) are the sole cytoskeletal components responsible for organizing acentriolar spindles. However, our recent work demonstrates that F-actin also plays a key role in regulating polar MTOC organization and ensuring the fidelity of meiotic spindle assembly. The mechanisms by which F-actin functions at the spindle, and how it interacts with MTs to control polar MTOC organization remain poorly understood, representing a critical gap in our knowledge of meiotic spindle formation. Traditionally, F-actin was thought to be the sole cytoskeletal regulator for spindle positioning and spindle migration toward the cortex in mammalian oocytes. This cortical migration is essential for asymmetric cell division, allowing the extrusion of a small polar body while retaining the majority of cytoplasmic material in the egg to support embryo development after fertilization. We recently identified a novel class of MTOCs, termed mcMTOCs, and found that mcMTOC-nucleated MTs counteract F-actin-mediated forces to regulate initial spindle positioning at the oocyte center and its timely migration. However, it remains unclear how mcMTOCs functionally differ from polar MTOCs and how MTs and F-actin interact to coordinate spindle positioning and migration. This proposal establishes the foundations for our long-term goal: to understand how two critical events during oocyte meiosis —spindle assembly and positioning — are regulated in the absence of centrioles to ensure accurate chromosome segregation and successful asymmetric cell division. To achieve this, we will employ state-of-the-art approaches, including transgenic mouse models, genetic manipulation, optogenetic manipulation and cutting-edge live imaging technologies, to pursue three critical goals: (1) Define how mcMTOCs are spatiotemporally regulated to regulate spindle positioning and migration, (2) elucidate how MTs and F-actin interact at the molecular level to regulate spindle positioning, and (3) determine how spindle-localized F-actin is regulated to ensure the fidelity of meiotic spindle formation. Given that chromosome segregation errors during oocyte meiosis are common and lead to aneuploidy, a major cause of developmental disorders and miscarriage, these studies have the potential to significantly advance our basic understanding of two fundamental processes — spindle formation and positioning — during meiosis whilst simultaneously shedding light on why oocyte meiosis is notoriously error-prone.


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 = $407,219 )
2026	2026	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	6	7/29/2026	COMPETING CONTINUATION	$407,219
														Subtotal = $407,219

Issue Date FY: 2025 ( Subtotal = $384,247 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	001	5	8/18/2025	NON-COMPETING CONTINUATION	$384,247
2025	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	4	6/2/2025	TERMINATION	$0
														Subtotal = $384,247

Issue Date FY: 2024 ( Subtotal = $475,273 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	3	8/19/2024	SUPPLEMENT FOR EXPANSION	$6,986
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	001	4	8/21/2024	NON-COMPETING CONTINUATION	$384,451
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	002	4	8/22/2024	SUPPLEMENT FOR EXPANSION	$83,836
														Subtotal = $475,273

Issue Date FY: 2023 ( Subtotal = $384,649 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	3	8/17/2023	NON-COMPETING CONTINUATION	$384,649
														Subtotal = $384,649

Issue Date FY: 2022 ( Subtotal = $628,346 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	001	2	8/30/2022	NON-COMPETING CONTINUATION	$379,191
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	1	6/9/2022	SUPPLEMENT FOR EXPANSION	$249,155
														Subtotal = $628,346

Issue Date FY: 2021 ( Subtotal = $376,553 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	1	8/11/2021	NEW	$376,553
														Subtotal = $376,553

Grand Total All Awards = $2,656,287

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Mechanisms underpinning meiotic spindle formation and behavior

Award Number: R35GM142537

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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