Maternal TDP43 orchestrates nuclear speckle assembly and zygotic splicing activation during oocyte-to-embryo transition in mice

Sep 30, 2026

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Zygotic splicing activation (ZSA) is a key mRNA post-transcriptional step during the maternal-to-zygotic transition, yet its regulators and mechanisms remain unclear. This study shows that nuclear speckles (NS) are newly established at the 2-cell stage in mice and align with the ZSA timing. NS localization is partially adjacent to, but mutually exclusive with, TDP43, whose function relies on liquid–liquid phase separation. TDP43 condensation-deficient form drives NS regulation, and maternal TDP43 loss disrupts NS assembly, causing exon-skipping failure and impaired totipotency–pluripotency conversion, while TDP43 excess enlarges NS and causes excessive skipping, producing bidirectional ZSA disorders and early 2-cell arrest.

LanguageEnglish

CategoryHealthcare

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Reading Time48 min

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Abstract

Graphical abstract

Introduction

Maternal TDP43 orchestrates nuclear speckle assembly and zygotic splicing activation during oocyte-to-embryo transition in mice Zuo-Qi Deng 1 ,†, Zhi-Yan Jiang1 ,†, Yu-Ke Wu 1 , Yun-Wen Wu 1 , Hua Zhang1 , Lu Chen 1,2 , Zhi-Yi Li3 , Li-Ling Liu4 ,* , Heng-Yu Fan 1,4 ,* 1Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China 2 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China 3 Department of Computer Science and Engineering, College of Engineering, The Ohio State University-Columbus, Columbus, OH 43210, United States 4 Department of Reproductive Medicine and Genetics Center, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, China ∗ To whom correspondence should be addressed. Email: [hyfan@zju.edu.cn](hyfan@zju.edu.cn) Correspondence may also be addressed to Li-Ling Liu. Email: [liulilingnn@126.com](liulilingnn@126.com) †The first two authors should be regarded as Joint First Authors. Abstract Zygotic splicing activation (ZSA) is a crucial process of mRNA post-transcriptional regulation during maternal-to-zygotic transition, ensuring normal embryonic development. However, the key factors and mechanisms underlying ZSA regulation remain unclear. We observed that the nuclear speckle (NS), a key splicing region, was newly established at the 2-cell stage in mice and was consistent with the ZSA period. Moreover, NS and TAR DNA-binding protein-43 (TDP43) always exhibited a partially adjacent and mutually exclusive localization relationship. TDP43 performed its function through liquid–liquid phase separation. The condensation-deficient state of TDP43 was the active form involved in NS regulation in 2-cell embryos. Additionally, TDP43 could also interact with both transcribed RNAs associated with NS and directly with NS proteins. Maternal TDP43 deficiency led to the failure of NS assembly in 2-cell embryos, resulting in the inability to skip exons during transcript splicing. In contrast, ectopic expression of TDP43 in zygotes led to abnormal enlargement of the NS, resulting in excessive skipping of transcript exons. Both bidirectional ZSA disorders led to 2-cell arrest during early embryogenesis. ZSA defects caused by TDP43 deficiency also impaired cell totipotency-pluripotency conversion. In this study, we identified an NS upstream regulatory factor, TDP43, which helps maintain the balance of ZSA, providing a new perspective on the post-transcriptional regulation of early embryos. Graphical abstract TDP43 deficiency Normal TDP43 excess Normal splicing 2-cell arrest 2-cell arrest × × ~~ ~~~~ ~~ Blastocyst Exon skipping failure Excessive exon skipping Introduction Fertilization is the origin of life and is accompanied by the reprogramming of transcripts, including the degradation of maternal mRNA and the initial production of zygotic mRNA. This process is defined as maternal-to-zygotic transition (MZT) [1]. Maternal mRNAs are fundamental for oocyte development, and their clearance determines the developmental competence of fertilized eggs. Defects in maternal factor- Received: May 12, 2025. Revised: July 30, 2025. Accepted: July 31, 2025 © The Author(s) 2026. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Deng et al. mediated mRNA decay (M-decay) or zygotic factor-mediated mRNA decay (Z-decay) can lead to arrest in embry

FAQs

What role does ZSA play during maternal-to-zygotic transition?

Zygotic splicing activation is a crucial mRNA post-transcriptional regulation process that supports normal embryonic development during the maternal-to-zygotic transition.

How is nuclear speckle (NS) assembly related to the 2-cell stage?

NS is newly established at the 2-cell stage in mice, and its timing is consistent with the ZSA period, linking NS assembly to activation of splicing.

What happens to splicing when maternal TDP43 is deficient or in excess?

Maternal TDP43 deficiency prevents proper NS assembly in 2-cell embryos and causes failure to skip exons during transcript splicing. In contrast, ectopic TDP43 expression enlarges NS and leads to excessive exon skipping, both resulting in early 2-cell arrest.

Sep 30, 2026

Uploaded by Bintang