bims-mazytr 2025-03-16 papers

bims-mazytr

Biomed News

on Maternal‐to‐zygotic transition

Issue of 2025–03–16
eightteen papers selected by
川一刀

Dynamics of replication timing during mammalian development.
Transposition element MERVL regulates DNA demethylation through TET3 in oxidative-damaged mouse preimplantation embryos.
Maternal control of embryonic dorsal organizer in vertebrates.
Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity.
Geometric, cell cycle and maternal-to-zygotic transition-associated YAP dynamics during preimplantation embryo development.
Programming of pluripotency and the germ line co-evolved from a Nanog ancestor.
Whole-genome transcriptome and DNA methylome analyses reveal molecular abnormalities during the oocyte-to-embryo transition in preimplantation embryos derived from prepubertal lamb oocytes.
Post-transcriptional regulation in early cell fate commitment of germ layers.
Generative model for the first cell fate bifurcation in mammalian development.
Single-nucleus multiomics reveals the gene regulatory networks underlying sex determination of murine primordial germ cells.
Extra-embryonic mesoderm during development and in in vitro models.
GSK3 coordinately regulates mitochondrial activity and nucleotide metabolism in quiescent oocytes.
The asymmetric expression of HSPA2 in blastomeres governs the first embryonic cell-fate decision.
Deficiency of UBE3D in mice leads to severe embryonic abnormalities and disrupts the mRNA of Homeobox genes via CPSF3.
Measuring and manipulating mechanical forces during development.
Hyper-ovulation in an ovarian-specific transgenic mouse model.
Comparatively profiling the transcriptome of human, Porcine and mouse oocytes undergoing meiotic maturation.
Mitochondrial replacement techniques to resolve mitochondrial dysfunction and ooplasmic deficiencies: where are we now?

Trends Genet. 2025 Mar 12. pii: S0168-9525(25)00026-5. [Epub ahead of print]

Dynamics of replication timing during mammalian development.

Tsunetoshi Nakatani.

  Recent developments in low-input genomics techniques have greatly advanced the analysis of the order in which DNA is replicated in the genome - that is, replication timing (RT) - and its interrelationships with other processes. RT correlates or anticorrelates with genomic-specific parameters such as gene expression, chromatin accessibility, histone modifications, and the 3D structure of the genome, but the significance of how they influence each other and how they relate to biological processes remains unclear. In this review I discuss the results of recent analyses of RT, the time at which it is remodeled and consolidated during embryogenesis, how it influences development and differentiation, and the regulatory mechanisms and factors involved.

Keywords:  3D genome organization; Rif1; embryonic development; replication stress; replication timing

DOI:  https://doi.org/10.1016/j.tig.2025.01.010
Mol Med. 2025 Mar 12. 31(1): 95

Transposition element MERVL regulates DNA demethylation through TET3 in oxidative-damaged mouse preimplantation embryos.

Lihong Liu, Siyao Ha, Dan Cao, MingQing Li, Zhiling Li.

  Transposable elements (TEs) comprise approximately half of eukaryotic genomes and significantly contribute to genome plasticity. In this study, we focused on a specific TE, MERVL, which exhibits particular expression during the 2-cell stage and commonly serves as an indicator of embryonic totipotency. However, its precise role in embryo development remains mysterious. We utilized DRUG-seq to investigate the effects of oxidative damage on genes and TEs expression. Our findings revealed that exposure to hydrogen peroxide (H2O2) could induce DNA damage, apoptosis, and incomplete DNA demethylation in embryos, which were potentially associated with MERVL expression. To further explore its function, antisense nucleotides (ASO) targeting MERVL were constructed to knockdown the expression in early embryos. Notably, this knockdown led to the occurrence of DNA damage and apoptosis as early as the 2-cell stage, consequently reducing the number of embryos that could progress to the blastocyst stage. Moreover, we discovered that MERVL exerted an influence on the reprogramming of embryonic DNA methylation. In MERVL-deficient embryos, the activity of the DNA demethylase ten-eleven translocation 3 (TET3) was suppressed, resulting in impaired demethylation when compared to normal development. This impairment might underpin the mechanism that impacts embryonic development. Collectively, our study not only verified the crucial role of MERVL in embryonic development but also probed its regulatory function in DNA methylation reprogramming, thereby laying a solid foundation for further investigations into MERVL's role.

Keywords:  DNA methylation; MERVL; Oxidative damage; TET3

DOI:  https://doi.org/10.1186/s10020-025-01143-3
Cells Dev. 2025 Mar 07. pii: S2667-2901(25)00027-0. [Epub ahead of print] 204020

Maternal control of embryonic dorsal organizer in vertebrates.

Jing Chen, Anming Meng.

  The establishment of the body axis and developmental blueprint in embryos has remained to be a central question in developmental biology, captivating scientists for centuries. A milestone in this field was achieved in 1924 when Hans Spemann and Hilde Mangold discovered the dorsal organizer for embryonic body axis formation in amphibians. Since then, extensive studies have demonstrated that the dorsal organizer is evolutionarily conserved in vertebrates. This organizer functions as a signaling center, directing adjacent cells toward specific fates and orchestrating pattern formation to establish the embryonic axis. After 70 years since the discovery of the organizer, studies in different model animal species had revealed that locally activated β-catenin signaling during blastulation plays an indispensable role in organizer induction. Then, efforts have been made to identify initiators of β-catenin activation in blastulas. Now, it appears that maternal Huluwa, a transmembrane protein, is a bona fide organizer inducer at least in teleost fish and frog, which can activate downstream signaling pathways, including but probably not limited to β-catenin pathway. More studies are needed to decode the complete molecular network controlling organizer induction.

Keywords:  Dorsal determinants; Huluwa; Maternal factor; Organizer; β-catenin

DOI:  https://doi.org/10.1016/j.cdev.2025.204020
Elife. 2025 Mar 13. pii: RP102226. [Epub ahead of print]13

Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity.

Shihui Chen, Carolyn Marie Phillips.

  RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.

Keywords:  C. elegans; argonaute; chromosomes; gene expression; small RNAs

DOI:  https://doi.org/10.7554/eLife.102226
bioRxiv. 2025 Feb 27. pii: 2025.02.27.640568. [Epub ahead of print]

Geometric, cell cycle and maternal-to-zygotic transition-associated YAP dynamics during preimplantation embryo development.

Madeleine Chalifoux, Maria Avdeeva, Eszter Posfai.

  During the first cell fate decision in mammalian embryos the inner cell mass cells, which will give rise to the embryo proper and other extraembryonic tissues, segregate from the trophectoderm cells, the precursors of the placenta. Cell fate segregation proceeds in a gradual manner encompassing two rounds of cell division, as well as cell positional and morphological changes. While it is known that the activity of the Hippo signaling pathway and the subcellular localization of its downstream effector YAP dictate lineage specific gene expression, the response of YAP to these dynamic cellular changes remains incompletely understood. Here we address these questions by quantitative live imaging of endogenously tagged YAP while simultaneously monitoring geometric cellular features and cell cycle progression throughout cell fate segregation. We apply a probabilistic model to our dynamic data, providing a quantitative characterization of the mutual effects of YAP and cellular relative exposed area, which has previously been shown to correlate with subcellular YAP localization in fixed samples. Additionally, we study how nuclear YAP levels are influenced by other factors, such as the decreasing pool of maternally provided YAP that is partitioned to daughter cells through cleavage divisions, cell cycle-associated nuclear volume changes, and a delay after divisions in adjusting YAP levels to new cell positions. Interestingly, we find that establishing low nuclear YAP levels required for the inner cell mass fate is largely achieved by passive cell cycle-associated mechanisms. Moreover, contrary to expectations, we find that mechanical perturbations that result in cell shape changes do not influence YAP localization in the embryo. Together our work identifies how various inputs are integrated over a dynamic developmental time course to shape the levels of a key molecular determinant of the first cell fate choice.

Keywords:  YAP; cell fate; dynamic Bayesian networks; live imaging; mouse; preimplantation

DOI:  https://doi.org/10.1101/2025.02.27.640568
Cell Rep. 2025 Mar 07. pii: S2211-1247(25)00167-6. [Epub ahead of print]44(3): 115396

Programming of pluripotency and the germ line co-evolved from a Nanog ancestor.

Darren Crowley, Luke Simpson, Jodie Chatfield, Teri Forey, Cinzia Allegrucci, Fei Sang, Nadine Holmes, Grigory Genikhovich, Ulrich Technau, Doreen Cunningham, Elena Silva, Nicholas Mullin, James E Dixon, Matthew Loose, Ramiro Alberio, Andrew D Johnson.

  Francois Jacob proposed that evolutionary novelty arises through incremental tinkering with pre-existing genetic mechanisms. Vertebrate evolution was predicated on pluripotency, the ability of embryonic cells to form somatic germ layers and primordial germ cells (PGCs). The origins of pluripotency remain unclear, as key regulators, such as Nanog, are not conserved outside of vertebrates. Given NANOG's role in mammalian development, we hypothesized that NANOG activity might exist in ancestral invertebrate genes. Here, we find that Vent from the hemichordate Saccoglossus kowalevskii exhibits NANOG activity, programming pluripotency in Nanog-/- mouse pre-induced pluripotent stem cells (iPSCs) and NANOG-depleted axolotl embryos. Vent from the cnidarian Nematostella vectensis showed partial activity, whereas Vent from sponges and vertebrates had no activity. VENTX knockdown in axolotls revealed a role in germline-competent mesoderm, which Saccoglossus Vent could rescue but Nematostella Vent could not. This suggests that the last deuterostome ancestor had a Vent gene capable of programming pluripotency and germline competence.

Keywords:  CP: Developmental biology; CP: Genomics; evolution; germline; hemichordates; iPSC; mesoderm; mouse embryonic stem cells; nanog; pluripotency; vent; vertebrate

DOI:  https://doi.org/10.1016/j.celrep.2025.115396
Biol Reprod. 2025 Mar 09. pii: ioaf045. [Epub ahead of print]

Whole-genome transcriptome and DNA methylome analyses reveal molecular abnormalities during the oocyte-to-embryo transition in preimplantation embryos derived from prepubertal lamb oocytes.

Qi Qi, Jiangyue Bian, Junjin Li, Kexiong Liu, Fengxiang Yan, Jian Hou.

  The juvenile in vitro embryo transfer (JIVET) technology holds the potential to accelerate livestock breeding. However, its application is limited due to the weak in vitro development of oocytes and embryos from prepubertal lambs. To dissect the regulatory networks of gene expression of sheep in vitro embryos and identify the defects in gene expression in prepubertal lamb embryos during the oocyte-to-embryo transition (OET), full-length RNA sequencing (RNA-seq) and whole-genome bisulfite sequencing (WGBS) based on trace cells were conducted on in vitro-derived embryos generated from adult sheep and prepubertal lamb oocytes. We found that the maternal mRNA degradation occurred selectively in adult sheep embryos in multiple waves and was most completed until the morula stage. Major embryonic genome activation (EGA) was found to occur at the morula stage. By comparing with the patterns of adult embryos, we observed incomplete maternal mRNA degradation and abnormal EGA in lamb embryos and analyzed their potential molecular mechanisms. Furthermore, we explored dynamic DNA methylation concerning the paternal and maternal genomes during the preimplantation development of sheep embryos, revealing the negative regulatory role of promoter DNA methylation on EGA process. Lamb embryos generally displayed higher DNA methylation levels than adults, potentially repressing the EGA gene expression, especially the genes associated with ribosomal and mitochondrial organization. We also found abnormalities in the methylation status of imprinted genes in lamb embryos. Our findings advance the understanding of sheep in vitro embryo development and offer insights for improving the JIVET technology in livestock.

Keywords:  full-length rna sequencing; juvenile in vitro embryo transfer; prepubertal lamb; sheep; whole-genome bisulfite sequencing

DOI:  https://doi.org/10.1093/biolre/ioaf045
BMC Genomics. 2025 Mar 08. 26(1): 225

Post-transcriptional regulation in early cell fate commitment of germ layers.

Rubens Gomes-Júnior, Cintia Delai da Silva Horinouchi, Aruana Fagundes Fiuza Hansel-Fröse, Annanda Lyra Ribeiro, Isabela Tiemy Pereira, Lucia Spangenberg, Bruno Dallagiovanna.

   BACKGROUND: Cell differentiation during development is orchestrated by precisely coordinated gene expression programs. While some regulatory mechanisms are well understood, there is a significant room to explore unresolved aspects of lineage choice and cell-fate decisions, as many events in these processes are still not fully elucidated. Given that, gene expression is influenced not only by transcriptional control but also by post-transcriptional events. Here, we described the presence of post-transcriptional regulation on gene expression during lineage commitment across all three embryonic germ layers. We employed monolayer differentiation protocols to map early transcriptional and post-transcriptional events in human embryonic stem cell specification. This approach included obtaining representative populations from the three germ layers, followed by sequencing of both polysome-bound and total RNAs.
RESULTS: We characterized our model by its unique expression profile and the presence of specific markers for each differentiation. RNA sequencing revealed a consistent pattern of gene upregulated and downregulated when comparing the transcriptome and translatome during the differentiation of all three germ layers. By comparing these datasets, we identified genes subjected to post-transcriptional regulation in all germ layer differentiations and categorized the nature of this regulation. GO analysis demonstrated that polysome profiling serves as a complementary technique, capturing nuances that may be overlooked when analyzing only the transcriptome. Finally, we directly compared the transcriptome and translatome to identify genes actively recruited to the translation machinery, uncovering unique features specific to each germ layer.
CONCLUSIONS: Substantial post-transcriptional modulation was found during germ layer commitment, emphasizing the translatome potency in capturing nuanced gene expression regulation. These findings highlight the post-transcriptional regulation's critical role in early embryonic development, offering new insights into the molecular mechanisms of cell differentiation.

Keywords:  Embryology; Germ layer; Human development; Polysome profiling; Post-transcriptional regulation

DOI:  https://doi.org/10.1186/s12864-025-11400-8
bioRxiv. 2025 Feb 25. pii: 2025.02.24.639895. [Epub ahead of print]

Generative model for the first cell fate bifurcation in mammalian development.

Maria Avdeeva, Madeleine Chalifoux, Bradley Joyce, Stanislav Y Shvartsman, Eszter Posfai.

The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in preimplantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asyn-chronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, key transcription factors of TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate bifurcations in mouse development.

DOI: https://doi.org/10.1101/2025.02.24.639895
Elife. 2025 Mar 10. pii: RP96591. [Epub ahead of print]13

Single-nucleus multiomics reveals the gene regulatory networks underlying sex determination of murine primordial germ cells.

Adriana K Alexander, Karina F Rodriguez, Yu-Ying Chen, Ciro Amato, Martin A Estermann, Barbara Nicol, Xin Xu, Humphrey H C Yao.

  Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial germ cells (PGCs) are the bipotential precursors of mature gametes that commit to an oogenic or spermatogenic fate in response to sex-determining cues from the fetal gonad. The critical processes required for PGCs to integrate and respond to signals from the somatic environment in gonads are not well understood. In this study, we developed the first single-nucleus multiomics map of chromatin accessibility and gene expression during murine PGC development in both XX and XY embryos. Profiling of cell-type-specific transcriptomes and regions of open chromatin from the same cell captured the molecular signatures and gene networks underlying PGC sex determination. Joint RNA and ATAC data for single PGCs resolved previously unreported PGC subpopulations and cataloged a multimodal reference atlas of differentiating PGC clusters. We discovered that regulatory element accessibility precedes gene expression during PGC development, suggesting that changes in chromatin accessibility may prime PGC lineage commitment prior to differentiation. Similarly, we found that sexual dimorphism in chromatin accessibility and gene expression increased temporally in PGCs. Combining single-nucleus sequencing data, we computationally mapped the cohort of transcription factors that regulate the expression of sexually dimorphic genes in PGCs. For example, the gene regulatory networks of XX PGCs are enriched for the transcription factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX. Sex-specific enrichment of the forkhead-box and POU6 families of transcription factors was also observed in XY PGCs. Finally, we determined the temporal expression patterns of WNT, BMP, and RA signaling during PGC sex determination, and our discovery analyses identified potentially new cell communication pathways between supporting cells and PGCs. Our results illustrate the diversity of factors involved in programming PGCs toward a sex-specific fate.

Keywords:  developmental biology; germ cell; gonad; mouse; ovary; primordial germ cells; sex differentiation; single cell sequencing; testis

DOI:  https://doi.org/10.7554/eLife.96591
Development. 2025 Mar 01. pii: DEV204624. [Epub ahead of print]152(5):

Extra-embryonic mesoderm during development and in in vitro models.

Eliana Nehme, Amitesh Panda, Isabelle Migeotte, Vincent Pasque.

  Extra-embryonic tissues provide protection and nutrition in vertebrates, as well as a connection to the maternal tissues in mammals. The extra-embryonic mesoderm is an essential and understudied germ layer present in amniotes. It is involved in hematopoiesis, as well as in the formation of extra-embryonic structures such as the amnion, umbilical cord and placenta. The origin and specification of extra-embryonic mesoderm are not entirely conserved across species, and the molecular mechanisms governing its formation and function are not fully understood. This Review begins with an overview of the embryonic origin and function of extra-embryonic mesoderm in vertebrates from in vivo studies. We then compare in vitro models that generate extra-embryonic mesoderm-like cells. Finally, we discuss how insights from studying both embryos and in vitro systems can aid in designing even more advanced stem cell-based embryo models.

Keywords:  Embryonic development; Evolution; Extra-embryonic mesoderm; Model organisms; Stem cell-based embryo models

DOI:  https://doi.org/10.1242/dev.204624
Biol Open. 2025 Mar 06. pii: bio.061815. [Epub ahead of print]

GSK3 coordinately regulates mitochondrial activity and nucleotide metabolism in quiescent oocytes.

Leah Eller, Lei Wang, Mehmet Oguz Gok, Helin Hocaoglu, Shenlu Qin, Parul Gupta, Matthew H Sieber.

  As cells transition between periods of growth and quiescence, their metabolic demands change. During this transition, cells must coordinate changes in mitochondrial function with the induction of biosynthetic processes. Mitochondrial metabolism and nucleotide biosynthesis are key rate-limiting factors in regulating early growth. However, it remains unclear what coordinates these mechanisms in developmental systems. Here, we show that during quiescence, as mitochondrial activity drops, nucleotide breakdown increases. However, at fertilization, mitochondrial oxidative metabolism and nucleotide biosynthesis are coordinately activated to support early embryogenesis. We have found that the serine/threonine kinase GSK3 is a key factor in coordinating mitochondrial metabolism with nucleotide biosynthesis during transitions between quiescence and growth. Silencing GSK3 in quiescent oocytes causes increased levels of mitochondrial activity and a shift in the levels of several redox metabolites. Interestingly, silencing GSK3 in quiescent oocytes also leads to a precocious induction of nucleotide biosynthesis in quiescent oocytes. Taken together, these data indicate that GSK3 functions to suppress mitochondrial oxidative metabolism and prevent the premature onset of nucleotide biosynthesis in quiescent eggs. These data reveal a key mechanism that coordinates mitochondrial function and nucleotide synthesis with fertilization.

Keywords:  Drosophila; Embryo; Metabolism; Mitochondria; Oocyte

DOI:  https://doi.org/10.1242/bio.061815
Elife. 2025 Mar 10. pii: RP100730. [Epub ahead of print]13

The asymmetric expression of HSPA2 in blastomeres governs the first embryonic cell-fate decision.

Jiayin Gao, Jiawei Wang, Shiyu Liu, Jinzhu Song, Chuanxin Zhang, Boyang Liu, Keliang Wu.

  The first cell-fate decision is the process by which cells of an embryo take on distinct lineage identities for the first time, thus representing the beginning of developmental patterning. Here, we demonstrate that the molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, is asymmetrically expressed in the late 2-cell stage of mouse embryos. The knockdown of Hspa2 in one of the 2-cell blastomeres prevented its progeny predominantly towards the inner cell mass (ICM) fate. In contrast, the overexpression of Hspa2 in one of the 2-cell blastomeres did not induce the blastomere to differentiate towards the ICM fate. Furthermore, we demonstrated that HSPA2 interacted with CARM1 and its levels correlated with ICM-associated genes. Collectively, our results identify HSPA2 as a critical early regulator of the first cell-fate decision in mammalian 2-cell embryos.

Keywords:  CARM1; HSPA2; developmental biology; embryo; first cell-fate decision; inner cell mass; mouse

DOI:  https://doi.org/10.7554/eLife.100730
Cell Death Discov. 2025 Mar 12. 11(1): 99

Deficiency of UBE3D in mice leads to severe embryonic abnormalities and disrupts the mRNA of Homeobox genes via CPSF3.

Yiwei Mi, Lu Yan, Yu Wu, Yufang Zheng.

Neurulation is a crucial event during vertebrate early embryogenesis, and abnormalities in this process can result in embryonic lethality or congenital disorders, such as neural tube defects. Through our previous phenotypic-driven screening in mice, we have identified UBE3D as a key factor for the neurulation process. By generating Ube3d knockout mice using CRISPR/Cas9 technology, we observed that homozygous mice exhibited severe growth retardation and malformation, ultimately dying between E10.5 to E11.5. In contrast to their wild-type and heterozygote littermates, homozygous embryos displayed small heads and unturned caudal neural tubes at E9.5. Our in situ hybridization and immunofluorescence experiments revealed high expression of UBE3D in the forebrain, neural tube, and heart at E9.5-10.5. Furthermore, RNA-seq analysis of the E10.5 embryos demonstrated that deficiency in UBE3D resulted in the downregulation of multiple Homeobox genes, including those specifically expressed in the forebrain and lumbosacral regions. We also discovered that UBE3D interacts with CPSF3, which is an endonuclease essential for the pre-mRNA 3' end process. UBE3D could de-ubiquitinate CPSF3, and a deficiency of UBE3D leads to reduced levels of CPSF3 in both mouse and human cells. Overexpression of dominant negative mutants of CPSF3 was found to partially reduce mRNA levels of several Homeobox genes. In summary, our findings highlight that UBE3D is critical for early embryonic development in mice.

DOI: https://doi.org/10.1038/s41420-025-02387-y
Nat Cell Biol. 2025 Mar 10.

Measuring and manipulating mechanical forces during development.

Clémentine Villeneuve, Kaitlin P McCreery, Sara A Wickström.

Tissue deformations are a central feature of development, from early embryogenesis, growth and building the body plan to the establishment of functional organs. These deformations often result from active contractile forces generated by cells and cell collectives, and are mediated by changes in their mechanical properties. Mechanical forces drive the formation of functional organ architectures, but they also coordinate cell behaviour and fate transitions, ensuring robustness of development. Advances in microscopy, genetics and chemistry have enabled increasingly powerful tools for measuring, generating and perturbing mechanical forces. Here we discuss approaches to measure and manipulate mechanical forces with a focus on developmental processes, ranging from quantification of molecular interactions to mapping the mechanical properties of tissues. We focus on contemporary methods, and discuss the biological discoveries that these approaches have enabled. We conclude with an outlook to methodologies at the interface of physics, chemistry and biology to build an integrated understanding of tissue morphodynamics.

DOI: https://doi.org/10.1038/s41556-025-01632-x
bioRxiv. 2025 Feb 25. pii: 2025.02.21.639591. [Epub ahead of print]

Hyper-ovulation in an ovarian-specific transgenic mouse model.

Luis C Muñiz, James Reilly, Melissa Spigelman, Carlos A Molina.

Ovulation is a fundamental prerequisite for achieving successful reproduction. In vertebrates, ovulation is controlled by the cyclical action of hormones, particularly the gonadotropins such as follicle stimulating hormone (FSH) and luteinizing hormone (LH). A critical component of the intracellular activity of these two hormones is relayed by the second messenger cAMP. Although it is well established that a family of transcription factors facilitate cAMP mediated gene expression, it remains unknown how these factors directly affect ovulation. In particular, the Inducible cAMP Early Repressor (ICER) has been implicated in the transcriptional repression of FSH inducible genes during folliculogenesis. Here we show, using an ovarian-specific transgenic mouse model that ICER potentiates ovulation. We observed a twofold rate increase in ovulation for transgenic mice when compared to the wild type in response to exogenous gonadotropin treatment. Furthermore, mature cycling transgenic mice display a significantly enhanced ovulation rate compared to the wild-type. The observed changes in ovulation in the transgenic females are accompanied by altered gonadotropins production and gene expression. Most significantly, the expression of inhibin alpha subunit (INHA) was found to be about 5-fold higher in the transgenic mice. These observations may aid in unraveling some of the molecular mechanisms underlying ovulation and be relevant to the development of novel reproductive technologies.
Summary Sentence: Generation of an FSH inducible ovarian specific FLAG-ICER-II© Tg Mice results in hyper-ovulation upon gonadotropin stimulation.

DOI: https://doi.org/10.1101/2025.02.21.639591
BMC Genomics. 2025 Mar 12. 26(1): 236

Comparatively profiling the transcriptome of human, Porcine and mouse oocytes undergoing meiotic maturation.

Naru Zhou, Xin Wang, Yi Xia, Zongliang Liu, Lei Luo, Rentao Jin, Xianhong Tong, Zhenhu Shi, Zhichao Wang, Heming Sui, Yangyang Ma, Yunsheng Li, Zubing Cao, Yunhai Zhang.

   BACKGROUND: Oocyte maturation is a critical process responsible for supporting preimplantation embryo development and full development to term. Understanding oocyte gene expression is relevant given the unique molecular mechanism present in this gamete. Comparative transcriptome analysis across species offers a powerful approach to uncover conserved and species-specific genes involved in the molecular regulation of oocyte maturation throughout evolution.
RESULTS: Transcriptome analysis identified 4,625, 3,824, 4,972 differentially expressed genes (DEGs) between the germinal vesicle (GV) and metaphase II (MII) stage in human, porcine and mouse oocytes respectively. These DEGs showed dynamic changes associated with oocyte maturation. Functional enrichment analysis revealed that the DEGs in all three species were mainly involved in DNA replication, cell cycle and redox regulation. Comparative transcriptome analysis identified 551 conserved DEGs in the three species with significant enrichment in mitochondria and mitochondrial intima.
CONCLUSIONS: This study provides a systematic comparative analysis of oocyte meiotic maturation in humans, pigs and mice identifying both conserved and species-specific patterns during oocyte meiosis. Our findings also implied that the selection of oocyte expressed genes among these three species could form a basis for further exploring their functional roles in human oocyte maturation.

Keywords:  Human; Mouse; Oocyte maturation; Pig; Transcriptome

DOI:  https://doi.org/10.1186/s12864-025-11431-1
Hum Reprod. 2025 Mar 13. pii: deaf034. [Epub ahead of print]

Mitochondrial replacement techniques to resolve mitochondrial dysfunction and ooplasmic deficiencies: where are we now?

Jessica Subirá, María José Soriano, Luis Miguel Del Castillo, María José de Los Santos.

  Mitochondria are the powerhouses of cell and play crucial roles in proper oocyte competence, fertilization, and early embryo development. Maternally inherited mitochondrial DNA (mtDNA) mutations can have serious implications for individuals, leading to life-threatening disorders and contribute to ovarian ageing and female infertility due to poor oocyte quality. Mitochondrial replacement techniques (MRTs) have emerged as a promising approach not only to replace defective maternal mitochondria in patients carrying mtDNA mutations, but also to enhance oocyte quality and optimize IVF outcomes for individuals experiencing infertility. There are two main categories of MRT based on the source of mitochondria. In the heterologous approach, mitochondria from a healthy donor are transferred to the recipient's oocyte. This approach includes several methodologies such as germinal vesicle, pronuclear, maternal spindle, and polar body transfer. However, ethical concerns have been raised regarding the potential inheritance of third-party genetic material and the development of heteroplasmy. An alternative approach to avoid these issues is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. However, the efficacy of AUGMENT has been debated following the results of a randomized clinical trial (RCT) that demonstrated no significant benefit over conventional IVF. Recent developments have focused on novel approaches based on autologous, non-invasively derived stem cells to address infertility. While these techniques show promising results, further RCTs are necessary to establish their effectiveness and safety for clinical use. Only after robust evidence becomes available could MRT potentially become a viable treatment option for overcoming infertility and enabling patients to have genetically related embryos. This review aims to provide an overview of the current state of MRTs in addressing low oocyte quality due to mitochondrial dysfunction.

Keywords:  female infertility; mitochondria; mitochondrial DNA; mitochondrial dysfunction; mitochondrial replacement; oocyte quality

DOI:  https://doi.org/10.1093/humrep/deaf034