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Dissecting the function of Nemp1, a nuclear envelope protein critical for mammalian fertility

Award Number: R01HD108639
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: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Dissecting the function of Nemp1, a nuclear envelope protein critical for mammalian fertility - PROJECT SUMMARY/ABSTRACT Generating high quality oocytes is critical for a woman's fertility and health, and for healthy offspring. Nuclear envelope membrane protein 1 (Nemp1) is a transmembrane protein of the inner nuclear envelope that we found is needed for fertility in a wide range of organisms. Loss of Nemp1 in mice leads to near-sterility of females, associated with loss of the oocytes that compose the primordial reserve. The remaining oocytes have poor developmental competence, with defects in chromosome segregation, chromatin compaction and completion of meiosis. GWAS studies show that variants in NEMP1 are associated with early menopause, suggesting the role of Nemp1 in fertility is conserved to humans. Our long term goal is to understand how Nemp1 functions at the nuclear envelope to promote oocyte quality and human fertility. In this grant we will use mouse models to determine why loss of Nemp1 leads to reduced ovarian reserve and poor developmental potential. We will determine when and how the ovarian reserve is lost, and define pathways involved in oocyte loss. We will conduct gain of function and loss-of-function studies, to determine which cells require Nemp1 in the mouse ovary. To identify Nemp1-interacting proteins, we will take advantage of novel mouse lines we have generated, which allow us to conduct affinity-purification coupled mass spectrometry from resting and growing oocytes. Our preliminary studies have revealed that Nemp1 accumulates into extremely large, regular foci at the nuclear envelope, uncovering a novel nuclear envelope structure in growing oocytes. Proteomic analysis will reveal other proteins that localize to these foci (which we term NECs). Super-resolution microscopy and electron microscopy will define the structure of Nemp1 clusters and the adjacent nuclear envelope. FRAP analysis will clarify the stability of the Nemp1 clusters, and associated proteins. Our preliminary data indicate that chromatin compaction is disrupted in Nemp1 mutant oocytes, and that transcription is deregulated. We will use RNAseq to define change in gene expression in Nemp1KO oocytes. We will use ChIP-seq to define changes in histone modifications in mutant oocytes, and determine alterations in 3D chromatin architecture using Hi-C. Our preliminary data indicate that a closely related gene, Nemp2, is upregulated in Nemp1KO oocytes, so we will explore the contribution of Nemp2 to Nemp1 mutant phenotypes. Our preliminary data indicate that the nucleoplasmic tail of Nemp1 can interact with chromatin in cultured cells: we will clarify the regions of Nemp1-chromatin interactions in oocytes, using transgenic DamID approaches. Together these studies will illuminate the function of the nuclear envelope, and the role of Nemp1 in supporting the creation of healthy oocytes.


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 = $565,330 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	001	3	4/14/2025	NON-COMPETING CONTINUATION	$56,534
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	3	10/31/2024	NON-COMPETING CONTINUATION	$508,796
														Subtotal = $565,330

Issue Date FY: 2024 ( Subtotal = $559,597 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$50,873
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	000	2	11/16/2023	NON-COMPETING CONTINUATION	$508,724
														Subtotal = $559,597

Issue Date FY: 2023 ( Subtotal = $583,024 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	1	12/15/2022	NEW	$583,024
														Subtotal = $583,024

Grand Total All Awards = $1,707,951

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Dissecting the function of Nemp1, a nuclear envelope protein critical for mammalian fertility

Award Number: R01HD108639

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: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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