(306) Investigating the Role of NEMP1 in Regulating Oocyte RNA Homeostasis and Genomic Stability

Investigating the Role of NEMP1 in Regulating Oocyte Nuclear RNA Homeostasis and Genomic Stability

Hui Zhang¹, Helen McNeill¹

1. Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St Louis, MO. USA

Abstract Text:

Female infertility is a major health issue affecting millions worldwide, with oocyte quality decline being a key factor. The nuclear envelope (NE) plays a crucial role in maintaining nuclear stability, regulating chromatin organization, and ensuring proper nucleocytoplasmic transport. Recent studies have identified Nuclear Envelope Membrane Protein 1 (NEMP1) as a critical regulator of nuclear envelope integrity and oocyte developmental competence. NEMP1 is highly expressed in oocytes across metazoans, and its deletion in mice (Nemp1−/−) leads to female sterility, while male fertility remains unaffected. Despite its essential role in reproduction, the molecular mechanisms by which NEMP1 influences oocyte quality remain largely unexplored.

Our study investigates the role of NEMP1 in regulating nuclear RNA homeostasis and genomic stability in growing oocytes. we observed that NEMP1 localizes to the oocyte nuclear envelope, forming distinct condensates, suggesting a structural role in nuclear organization. The absence of NEMP1 led to nuclear envelope deformations and chromatin abnormalities, raising the question of whether NEMP1 condensates provide mechanical support to maintain nuclear stability in oocytes. Given that oocyte growth is associated with increased RNA transcription and export, we hypothesized that NEMP1 may facilitate proper nuclear RNA dynamics. Immunoprecipitation-mass spectrometry (IP-MS) analysis revealed that NEMP1 interacts with nuclear export proteins, and single-molecule RNA FISH confirmed that the nuclear export of specific circular RNAs (circRNAs) (Man1a2_mus, Phf14_mus, Evi5_mus) is impaired in Nemp1−/− oocytes. These findings suggest that NEMP1 may play a role in coordinating RNA export, potentially linking nuclear envelope integrity to transcriptome regulation during oocyte maturation. Additionally, our study explored the role of NEMP1 in telomere organization. Telomere FISH and immunofluorescence staining showed that ~10% of telomeres colocalize with NEMP1 condensates in wild-type oocytes. However, in Nemp1−/− oocytes, telomeres displayed abnormal clustering, forming large telomere aggregates (TAs), a hallmark of genomic instability. Given that proper telomere distribution is essential for chromosome stability and meiotic progression, these findings suggest that NEMP1 is involved in telomere-nuclear envelope interactions, potentially regulating their spatial organization to maintain genomic integrity.

Together, these findings indicate that NEMP1 is essential for coordinating multiple nuclear functions, including RNA export, telomere organization, and nuclear membrane integrity. Disruptions in these processes in NEMP1-deficient oocytes may contribute to compromised developmental competence and female infertility. Ongoing research aims to determine whether nuclear export defects and telomere aggregation are direct consequences of defective nuclear membrane organization in Nemp1−/− oocytes. This study provides critical insights into the role of nuclear envelope proteins in reproductive aging and female fertility, with potential implications for therapeutic strategies targeting nuclear stability in aging oocytes.