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Cell-type specific inactivation of sumoylation during mouse spermatogenesis

Award Number: R15HD096759
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: 06/12/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Cell-type specific inactivation of sumoylation during mouse spermatogenesis - Abstract. Previous studies from our laboratory have obtained evidence implicating sumoylation in regulation of different events during spermatognenesis. SUMO is abundantly expressed in germ cells from different species, and the localization pattern suggests diverse and potentially multiple roles of sumoylation in testicular function. We have also performed a broad-spectrum cell-specific identification of SUMO targets in purified mouse germ cells. Numerous proteins with important roles during mitosis, meiosis and spermatid differentiation have been identified. Level of sumoylation correlated with the proliferation activity of germ cells. Notably, in mouse spermatocytes, inhibition of global sumoylation with the inhibitor Ginkgolic acid (GA) arrested cells at the G2/M1 checkpoint in vitro due to the inability of spermatocytes to condense chromatin and disassemble their synaptonemal complexes (SC). Our preliminary data show that Polo kinase1 (PLK1) and Aurora B (AURKB) are activated upon G2/M meiotic transition, but significantly inhibited upon inhibition of sumoylation. Since PLK1and AURKB are responsible for the disassembly of the SC and chromatin condensation, respectively, these kinases are "at the right place, at the right time" to at least, in part, explain the meiotic arrest. However, definite evidence regarding the importance of sumoylation and its targets in germ cells in vivo is lacking because of the embryonic lethality of mice with inactivated sumoylation machinery. The specific aims of the current application will be: 1) To perform a cell- specific inactivation of sumoylation and characterize the consequences of this inactivation in mitotic spermatogonia, meiotic spermatocytes and differentiating spermatids in vivo using a UBA2 (SUMO- activating enzyme) loxP mouse model that we possess as well as commercially available mouse models expressing Cre recombinase in the corresponding germ cells; 2) To dissect the molecular events regulated by sumoylation in spermatocytes through analysis of the activity, interacting partners and phosphorylation status of known downstream targets of PLK1 and AURKB upon inhibition of sumoylation in vivo and in vitro. Together, the proposed research and follow-up studies will advance knowledge across the field of germ cell biology by the characterization of post-translational modification networks necessary for the progression throughout spermatogenesis. A significant part of the proposed project will be conducted by undergraduate students who will have the opportunity to use state-of-the-art equipment, learn hypothesis generation and practice basic and advanced biomedical techniques. They will be involved in germ cell isolation, preparation of cell lysates, western blot, PCR, microscopy, and bioinformatics analyses. Opportunities to participate in research early in their careers will give students a better understanding of a career in science and will motivate them to pursue their education in STEM fields.


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: 2024 ( Subtotal = $0 )
2024	2019	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	12/15/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $45,000 )
2022	2022	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Child Health and Human Development Extramural Research	001	1	7/12/2022	SUPPLEMENT FOR EXPANSION	$45,000
2022	2019	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	6/23/2022	NEW	$0
														Subtotal = $45,000

Issue Date FY: 2019 ( Subtotal = $450,000 )
2019	2019	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	6/12/2019	NEW	$450,000
2019	2019	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Child Health and Human Development Extramural Research	001	1	8/15/2019	NEW	$0
														Subtotal = $450,000

Grand Total All Awards = $495,000

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Cell-type specific inactivation of sumoylation during mouse spermatogenesis

Award Number: R15HD096759

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: 06/12/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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