bims-mazytr 2025-04-06 papers

bims-mazytr

Biomed News

on Maternal‐to‐zygotic transition

Issue of 2025–04–06
seventeen papers selected by
川一刀

RNA Splicing and Alternative Polyadenylation Profile during Sheep Zygotic Genome Activation.
Epigenome dynamics in early mammalian embryogenesis.
ZNHIT3 Regulates Translation to Ensure Cell Lineage Differentiation in Mouse Preimplantation Development.
SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites.
No transcription, no problem: Protein phosphorylation changes and the transition from oocyte to embryo.
Alternative splicing dynamics during gastrulation in mouse embryo.
Pluripotent cell states and fates in human embryo models.
The genetics of preimplantation embryonic arrest: the role of aneuploidies.
Calcium signals shape metabolic control of H3K27ac and H3K18la to regulate EGA.
Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
Paternal contributions to mammalian zygote - Beyond sperm-oocyte fusion.
Oxygen level alters energy metabolism in bovine preimplantation embryos.
Activating the C. elegans egg: Molecular players, current knowledge, and unanswered questions.
From genes to patterns: a framework for modeling the emergence of embryonic development from transcriptional regulation.
Cellular and molecular regulations of oocyte selection and activation in mammals.
The mammalian egg's zona pellucida, fertilization, and fertility.
Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation.

Biol Reprod. 2025 Mar 28. pii: ioaf068. [Epub ahead of print]

RNA Splicing and Alternative Polyadenylation Profile during Sheep Zygotic Genome Activation.

Mingtian Deng, Hua Yang, Ying Chen, Nasser Ghanem, Yingnan Yang, Xiaowei Chen, Zhang JinHao, Feng Wang, Liqin Wang, Yanli Zhang.

  Zygotic genome activation (ZGA) is a critical biological step in mammalian early embryo development. However, ZGA initiation in sheep and the related sophisticated RNA metabolism remains largely unknown. Here, we observed extensive alterations in gene expression and DNA methylation patterns, along with elevated levels of RNA polymerase II (RNAPII) and its phosphorylation at serine 2 (RNAPII-Ser2P) at the 16-cell stage. Moreover, the embryos were blocked at the 16-cell stage embryo when treated with α-Amanitin, indicating that ZGA is initiated at the 16-cell stage in sheep in vitro fertilized embryos. To uncover the sophisticated RNA metabolism during ZGA, we conducted weighted gene co-expression network analysis and identified 1957 critical maternal genes, including TET3, UHRF1 and KIF2C. Using dapars analysis, we discovered 1058 and 933 lengthened alternative polyadenylation (APA) events during ZGA in sheep and mice. Specifically, genes exhibiting shorten APA were highly expressed at sheep 16-cell stage embryos and mouse 2-cell stage embryos. During ZGA in sheep and mice, 2675 and 1963 genes showed exon skipping, an alternative splicing (AS) events, which is related to RNA binding, translation, gamete generation, and reproduction. Of note, inhibition of AS led to 2-cell block in mice and 8/16-cell block in sheep. Moreover, 5-EU, RNAPII, and RNAPII-Ser2P signal were decreased in AS inhibited 2-cell embryos in mice, suggesting AS might regulate the ZGA process by crosstalk with RNAPII. In conclusion, our data confirmed ZGA initiation at the 16-cell stage embryos, and provides insights into the complex RNA metabolism during ZGA in mammals.

Keywords:  Zygotic genome activation; alternative polyadenylation; alternative splicing; sheep

DOI:  https://doi.org/10.1093/biolre/ioaf068
Nat Rev Genet. 2025 Apr 03.

Epigenome dynamics in early mammalian embryogenesis.

Adam Burton, Maria-Elena Torres-Padilla.

During early embryonic development in mammals, the totipotency of the zygote - which is reprogrammed from the differentiated gametes - transitions to pluripotency by the blastocyst stage, coincident with the first cell fate decision. These changes in cellular potency are accompanied by large-scale alterations in the nucleus, including major transcriptional, epigenetic and architectural remodelling, and the establishment of the DNA replication programme. Advances in low-input genomics and loss-of-function methodologies tailored to the pre-implantation embryo now enable these processes to be studied at an unprecedented level of molecular detail in vivo. Such studies have provided new insights into the genome-wide landscape of epigenetic reprogramming and chromatin dynamics during this fundamental period of pre-implantation development.

DOI: https://doi.org/10.1038/s41576-025-00831-4
Adv Sci (Weinh). 2025 Apr 03. e2413599

ZNHIT3 Regulates Translation to Ensure Cell Lineage Differentiation in Mouse Preimplantation Development.

Guanghui Yang, Qiliang Xin, Jurrien Dean.

  Upon fertilization, the mouse zygotic genome is activated and maternal RNAs as well as proteins are degraded. Early developmental programs are built on proteins encoded by zygotic mouse genes that are needed to guide early cell fate commitment. The box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing essential for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) is previously identified as a component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, it identifies Znhit3 as an early embryonic gene whose ablation reduces protein translation and prevents mouse embryos development beyond the morula stage. The absence of ZNHIT3 leads to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.

Keywords:  SMARM‐seq; ZNHIT3; box C/D snoRNA; embryo development; first cell fate commitment; ribosomal RNA; snoRNP complex; translation

DOI:  https://doi.org/10.1002/advs.202413599
Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102499

SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites.

Mingze Shi, Yingxue Huai, Tiantian Deng, Chuanxin Zhang, Jinzhu Song, Jiawei Wang, Yiwen Zhang, Zi-Jiang Chen, Han Zhao, Keliang Wu, Boyang Liu.

  Assisted reproductive technology (ART) is used widely and efficiently to treat infertility. During the ART procedure, one of the main factors affecting the success rate is abnormal development of preimplantation embryos. The establishment and maintenance of developmental competence are precisely regulated at different levels, while minor errors at early stages may result in adverse outcomes, including developmental arrest and implantation failure. As one of the major inputs, the regulatory mechanisms of metabolites in embryonic development are less known. In this study, we investigated the functional relevance of the metabolic enzyme serine hydroxymethyltransferase 2 (SHMT2) and deoxyribonucleotide (dNTP) metabolites in mouse preimplantation embryonic development. By using a well-characterized SHMT2 inhibitor, SHMT-IN-2, we effectively inhibited the catalytic activity of the SHMT2 enzyme, which led to developmental arrest at the pronuclear stage of the embryo. A low-input liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and applied for detecting dNTP content in embryos. We found that SHMT2 inhibition led to an insufficient dTTP supply and replication stress during the first mitotic cleavage, thereby causing failure of pronuclear fusion and developmental arrest. Our findings demonstrate a specific mechanism where, apart from building blocks of DNA, the availability of dNTPs contributes to the control of mouse preimplantation embryonic development.

Keywords:  MT: Oligonucleotides: Therapies and Applications; SHMT2; development; embryo; metabolism; nucleotide

DOI:  https://doi.org/10.1016/j.omtn.2025.102499
Curr Top Dev Biol. 2025 ;pii: S0070-2153(25)00010-9. [Epub ahead of print]162 165-205

No transcription, no problem: Protein phosphorylation changes and the transition from oocyte to embryo.

Jonathon M Thomalla, Mariana F Wolfner.

  Although mature oocytes are arrested in a differentiated state, they are provisioned with maternally-derived macromolecules that will start embryogenesis. The transition to embryogenesis, called 'egg activation', occurs without new transcription, even though it includes major cell changes like completing stalled meiosis, translating stored mRNAs, cytoskeletal remodeling, and changes to nuclear architecture. In most animals, egg activation is triggered by a rise in free calcium in the egg's cytoplasm, but we are only now beginning to understand how this induces the egg to transition to totipotency and proliferation. Here, we discuss the model that calcium-dependent protein kinases and phosphatases modify the phosphorylation landscape of the maternal proteome to activate the egg. We review recent phosphoproteomic mass spectrometry analyses that revealed broad phospho-regulation during egg activation, both in number of phospho-events and classes of regulated proteins. Our interspecies comparisons of these proteins pinpoints orthologs and protein families that are phospho-regulated in activating eggs, many of which function in hallmark events of egg activation, and others whose regulation and activity warrant further study. Finally, we discuss key phospho-regulating enzymes that may act apically or as intermediates in the phosphorylation cascades during egg activation. Knowing the regulators, targets, and effects of phospho-regulation that cause an egg to initiate embryogenesis is crucial at both fundamental and applied levels for understanding female fertility, embryo development, and cell-state transitions.

Keywords:  Calcineurin; Calcium; CamKII; Egg activation; Embryogenesis; Fertilization; Meiotic arrest; Oocyte; Post-translational control; Protein phosphorylation; Translation; Zygote

DOI:  https://doi.org/10.1016/bs.ctdb.2025.01.001
Sci Rep. 2025 Mar 31. 15(1): 10948

Alternative splicing dynamics during gastrulation in mouse embryo.

Wei Wang, Yu Zhang, Yuanyuan Zhai, Wuritu Yang, Yongqiang Xing.

  Alternative splicing (AS) plays an essential role in development, differentiation and carcinogenesis. However, the mechanisms underlying splicing regulation during mouse embryo gastrulation remain unclear. Based on spatial-temporal transcriptome and epigenome data, we detected the dynamics of AS and revealed its regulatory mechanisms across primary germ layers during mouse gastrulation, spanning developmental stages from E6.5 to E7.5. Subsequently, the dynamic expression of splicing factors (SFs) during gastrulation was characterized, while the expression patterns and functions of germ layer-specific SFs were identified. The results indicate that AS and differential alternative splicing events (DASEs) exhibit dynamic changes and are significantly abundant during the late stage of gastrulation. Similarly, SFs demonstrate stage-specific expression, with elevated levels observed during the middle and late stages of gastrulation. Epigenetic signals associated with SFs and AS sites demonstrate significant enrichment and undergo dynamic changes throughout gastrulation. Overall, this study offers a systematic analysis of AS during mouse gastrulation, identifies primary germ layer-specific AS events, and characterizes the expression patterns of SFs and the associated epigenetic signals. These findings enhance the understanding of the mechanisms underlying the formation of the three germ layers during mammalian gastrulation, with a focus on pre-mRNA AS.

Keywords:  Alternative splicing; Embryonic development; Epigenetic regulation; Mouse gastrulation; Splicing factors

DOI:  https://doi.org/10.1038/s41598-025-96148-7
Development. 2025 Apr 01. pii: dev204565. [Epub ahead of print]152(7):

Pluripotent cell states and fates in human embryo models.

Berna Sozen, Patrick P L Tam, Martin F Pera.

  Pluripotency, the capacity to generate all cells of the body, is a defining property of a transient population of epiblast cells found in pre-, peri- and post-implantation mammalian embryos. As development progresses, the epiblast cells undergo dynamic transitions in pluripotency states, concurrent with the specification of extra-embryonic and embryonic lineages. Recently, stem cell-based models of pre- and post-implantation human embryonic development have been developed using stem cells that capture key properties of the epiblast at different developmental stages. Here, we review early primate development, comparing pluripotency states of the epiblast in vivo with cultured pluripotent cells representative of these states. We consider how the pluripotency status of the starting cells influences the development of human embryo models and, in turn, what we can learn about the human pluripotent epiblast. Finally, we discuss the limitations of these models and questions arising from the pioneering studies in this emerging field.

Keywords:  Cell fate; Epiblast; Human embryo model; Peri-implantation development; Pluripotent stem cell

DOI:  https://doi.org/10.1242/dev.204565
Curr Opin Obstet Gynecol. 2025 Mar 24.

The genetics of preimplantation embryonic arrest: the role of aneuploidies.

Ludovica Picchetta, Katharina Spath, Antonio Capalbo, Christian Simon Ottolini.

PURPOSE OF THE REVIEW: Aneuploidy is a major cause of embryonic arrest. While meiotic aneuploidies, especially maternal, are a well-documented cause of embryo and fetal arrest, increasing evidence highlights the crucial role played by mitotic aneuploidies. This review explores the molecular and cellular pathways underlying these abnormalities, focusing on abnormal cleavage, chromatin cohesion, spindle stability, maternal effect genes, and mitochondria.
RECENT FINDINGS: Approximately half of human embryos cease development in vitro or shortly after transfer to the uterus. Genetic investigation of these embryos has highlighted that 90% of these exhibit aneuploidies. Surprisingly, most of these arise from errors during the early mitotic divisions of preimplantation embryos. These findings strongly correlate with disruptions of early cleavage possibly due to faulty spindle assembly or mitochondrial dysfunction during the in-vitro development. Moreover, maternal effects, such as faulty meiotic recombination and variants in maternal effect genes involved in the subcortical maternal complex, may further predispose the embryo to high rates of chromosomal imbalance.
SUMMARY: Meiotic and mitotic aneuploidies play a significant role in embryo arrest, yet their molecular and cellular origin are not well understood. Investigating these pathways may lead to interventions that could be developed to improve success rates with IVF or even fertility rates in general.

DOI: https://doi.org/10.1097/GCO.0000000000001020
bioRxiv. 2025 Mar 16. pii: 2025.03.14.643362. [Epub ahead of print]

Calcium signals shape metabolic control of H3K27ac and H3K18la to regulate EGA.

Virginia Savy, Paula Stein, Don Delker, Martín A Estermann, Brian N Papas, Zongli Xu, Lenka Radonova, Carmen J Williams.

  The use of assisted reproductive technologies (ART) has enabled the birth of over 9 million babies; but it is associated with increased risks of negative metabolic outcomes in offspring. Yet, the underlying mechanism remains unknown. Calcium (Ca2+) signals, which initiate embryo development at fertilization, are frequently disrupted in human ART. In mice, abnormal Ca2+ signals at fertilization impair embryo development and adult offspring metabolism. Changes in intracellular Ca2+ drive mitochondrial activity and production of metabolites used by the epigenetic machinery. For example, acetyl-CoA (derived mainly from pyruvate) and lactyl-CoA (derived from lactate) are used for writing H3K27ac and H3K18la marks that orchestrate initiation of development. Using both a genetic mouse model and treatment with ionomycin to raise intracellular Ca2+ of wild-type fertilized eggs, we found that excess Ca2+ at fertilization changes metabolic substrate availability, causing epigenetic changes that impact embryo development and offspring health. Specifically, increased Ca2+ exposure at fertilization led to increased H3K27ac levels and decreased H3K18la levels at the 1-cell (1C) stage, that persisted until the 2-cell (2C) stage. Ultralow input CUT&Tag revealed significant differences in H3K27ac and H3K18la genomic profiles between control and ionomycin groups. In addition, increased Ca2+ exposure resulted in a marked reduction in global transcription at the 1C stage that persisted through the 2C stage due to diminished activity of RNA polymerase I. Excess Ca2+ following fertilization increased pyruvate dehydrogenase activity (enzyme that converts pyruvate to acetyl-CoA) and decreased total lactate levels. Provision of exogenous lactyl-CoA before ionomycin treatment restored H3K18la levels at the 1C and 2C stages and rescued global transcription to control levels. Our findings demonstrate conclusively that Ca2+ dynamics drive metabolic regulation of epigenetic reprogramming at fertilization and alter EGA.

Keywords:  DOHaD; Metabolofertility; artificial oocyte activation (AOA); lactylation; zygotic genome activation (ZGA)

DOI:  https://doi.org/10.1101/2025.03.14.643362
Hum Reprod. 2025 Apr 02. pii: deaf050. [Epub ahead of print]

Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.

Paula Rubens, Anne Mayeur, Kalliopi Chatzovoulou, Nadine Gigarel, Sophie Monnot, Agnès Rötig, Arnold Munnich, Nelly Frydman, Julie Steffann.

   STUDY QUESTION: Is preimplantation genetic testing for mitochondrial DNA (mtDNA) disorders (PGT-mt) feasible at early compaction and blastocyst stages?
SUMMARY ANSWER: Pathogenic mtDNA variants segregate evenly among cell types and various lineages of a given embryo during preimplantation development, supporting the relevance of genetic analyses performed on Day 4 blastomere and on Day 5 or 6 trophectoderm (TE) samples.
WHAT IS KNOWN ALREADY: PGT-mt is validated at cleavage stage (Day 3 of development). However, its feasibility at later stages is questionable, as little is known regarding the segregation of pathogenic mtDNA variants during preimplantation development. Since mtDNA replication is silenced until the blastocyst stage (Day 5 or 6), uneven mtDNA segregation between preimplantation embryo cellular lineages known as a 'bottleneck' effect, cannot be excluded, posing a challenge for PGT-mt.
STUDY DESIGN, SIZE, DURATION: We analyzed 112 'mito' embryos carrying pathogenic mtDNA variants and 28 control embryos with mtDNA polymorphism. Heteroplasmy levels were assessed in single cells of the TE, in different parts of blastocysts (inner cell mass and TE), and at three time points of development, namely cleavage (Day 3), early compaction (Day 4), and blastocyst stages (Day 5 or 6).
PARTICIPANTS/MATERIALS, SETTING, METHODS: As part of clinical PGT, a blastomere biopsy was performed at cleavage or early compaction stages (Day 3 or 4) on 112 'mito' and 21/28 control embryos. Further analysis was carried out at Day 5 or 6 on 51 embryos deemed unsuitable for uterine transfer and donated to research. Heteroplasmy levels were determined by semi-quantitative PCR amplification of (i) the mtDNA pathogenic variants with additional enzymatic digestion or (ii) the mtDNA polymorphic hypervariable region 2.
MAIN RESULTS AND THE ROLE OF CHANCE: Here, we first show that mtDNA variants segregate evenly among blastomeres during early compaction (Day 4), supporting the feasibility of PGT-mt at this stage. We also found that mtDNA ratios remain stable between cleavage and blastocyst stages. Yet, the substantial variation of heteroplasmy levels occurring among single TE cells in 1/8 embryos suggests that PGT is only feasible when at least 5-10 cells are collected by standard TE biopsy.
LIMITATIONS, REASONS FOR CAUTION: This study sheds light on mtDNA segregation in human preimplantation embryo development. Its limitation lies in the scarcity of the material and the small number of embryos carrying a specific pathogenic mtDNA variant. Furthermore, the study of single cells from TE was performed on control embryos only.
WIDER IMPLICATIONS OF THE FINDINGS: By supporting the relevance of blastocyst biopsy in the context of PGT for pathogenic mtDNA variants, this study contributes to the general trend of postponing the biopsy to later stages of embryonic development. However, particular attention should be paid to the number of TE cells tested. Due to the potential variation of mutant load during in utero development, a control amniocentesis for evolutive pregnancies following the transfer of heteroplasmic embryos is still recommended.
STUDY FUNDING/COMPETING INTEREST(S): This work was funded by 'Association Française contre les Myopathies/AFM Téléthon' (22112, 24317, 28525); and EUR G.E.N.E. (No. ANR-17-EURE-0013). The authors have no competing interests to declare.
TRIAL REGISTRATION NUMBER: N/A.

Keywords:  heteroplasmy; human preimplantation embryo; mitochondria; mitochondrial DNA; morula biopsy; mtDNA segregation; pathogenic mtDNA variants; preimplantation genetic testing; trophectoderm biopsy

DOI:  https://doi.org/10.1093/humrep/deaf050
Curr Top Dev Biol. 2025 ;pii: S0070-2153(25)00038-9. [Epub ahead of print]162 387-446

Paternal contributions to mammalian zygote - Beyond sperm-oocyte fusion.

Peter Sutovsky, Michal Zigo, Filip Tirpak, Richard Oko.

  Contrary to a common misconception that the fertilizing spermatozoon acts solely as a vehicle for paternal genome delivery to the zygote, this chapter aims to illustrate how the male gamete makes other essential contributions , including the sperm borne-oocyte activation factors, centrosome components, and components of the sperm proteome and transcriptome that help to lay the foundation for pregnancy establishment and maintenance to term, and the newborn and adult health. Our inquiry starts immediately after sperm plasma membrane fusion with its oocyte counterpart, the oolemma. Parallel to and following sperm incorporation in the egg cytoplasm, some of the sperm structures (perinuclear theca) are dissolved and spent to induce development, others (nucleus, centriole) are transformed into zygotic structures enabling it, and yet others (mitochondrial and fibrous sheath, axonemal microtubules and outer dense fibers) are recycled as to not stand in its way. Noteworthy advances in this research include the identification of several sperm-borne oocyte activating factor candidates, the role of autophagy in the post-fertilization sperm mitochondrion degradation, new insight into zygotic centrosome origins and function, and the contributions of sperm-delivered RNA cargos to early embryo development. In concluding remarks, the unresolved issues, and clinical and biotechnological implications of sperm-vectored paternal inheritance are discussed.

Keywords:  Acrosome; Centrosome; Fertilization; Fibrous sheath; Infertility; Inheritance; Mitochondria; Outer dense fibers; Perinuclear theca; RNA; Sperm

DOI:  https://doi.org/10.1016/bs.ctdb.2025.02.002
Sci Rep. 2025 Apr 02. 15(1): 11327

Oxygen level alters energy metabolism in bovine preimplantation embryos.

Nina Boskovic, Marilin Ivask, Gamze Yazgeldi Gunaydin, Barış Yaşar, Shintaro Katayama, Andres Salumets, Tõnis Org, Ants Kurg, Karolina Lundin, Timo Tuuri, Carsten O Daub, Juha Kere.

Mammalian preimplantation embryo development is a complex sequence of events. This period of development is sensitive to oxygen (O2) levels that can affect various cellular processes. We compared the influence of O2 tension by culturing embryos either in normoxic (20% O2) or physiological hypoxic (6% O2) conditions, or sequential low O2 concentration starting with 6% O2 until 16-cell stage and then switching to ultrahypoxic conditions (2% O2). Due to ethical concerns, we used bovine as an animal model with a good similarity of embryogenesis to human. We found that the cleavage rate was not affected by O2 levels but there was a clear difference in blastocyst formation rate. In hypoxia, 36% of embryos reached blastocyst stage while in normoxia only 13%. In ultrahypoxia conditions only 4.6% of embryos developed up to blastocyst stage. Transcriptomic profiles showed that normoxic conditions slowed down oocyte transcript degradation which is a prerequisite for reprogramming of the embryonic cell lineages. There were also clear differences in the expression of key metabolic enzymes between hypoxic and normoxic conditions at the blastocyst stage. Both hypoxic and ultrahypoxic conditions seemed to induce appropriate energy production by upregulating genes involved in glycolysis and lipid metabolism typical to in vivo embryos. In contrast, normoxic conditions failed to upregulate glycolysis genes and only depended on oxidative phosphorylation metabolism. We conclude that constant hypoxia culture of in vitro embryos provided the highest blastocyst formation rate and appropriate energy metabolism. Normoxia altered the energy metabolism and decreased the blastocyst formation rate. Even though ultrahypoxia at blastocyst stage resulted in the lowest blastocyst formation, the transcriptional profile of surviving embryos was normal.

DOI: https://doi.org/10.1038/s41598-025-95990-z
Curr Top Dev Biol. 2025 ;pii: S0070-2153(25)00018-3. [Epub ahead of print]162 115-141

Activating the C. elegans egg: Molecular players, current knowledge, and unanswered questions.

Aimee Jaramillo-Lambert, Amber R Krauchunas.

  Egg activation is a global cellular change that, in combination with fertilization, transitions the differentiated, developmentally quiescent oocyte into a totipotent, developmentally active one-cell embryo. In C. elegans, key regulators of egg activation include egg-3, egg-4, egg-5, chs-1, and spe-11. Here we will review our current understanding of how these molecules, and others, ensure the robust activation of the egg by controlling meiosis, formation of the eggshell, and the block to polyspermy.

Keywords:  C. elegans; Calcium; EGG complex; Egg; Egg activation; Eggshell; Oocyte-to-embryo transition; Polyspermy; Spe

DOI:  https://doi.org/10.1016/bs.ctdb.2025.01.007
Front Cell Dev Biol. 2025 ;13 1522725

From genes to patterns: a framework for modeling the emergence of embryonic development from transcriptional regulation.

Jimena Garcia-Guillen, Ezzat El-Sherif.

  Understanding embryonic patterning, the process by which groups of cells are partitioned into distinct identities defined by gene expression, is a central challenge in developmental biology. This complex phenomenon is driven by precise spatial and temporal regulation of gene expression across many cells, resulting in the emergence of highly organized tissue structures. While similar emergent behavior is well understood in other fields, such as statistical mechanics, the regulation of gene expression in development remains less clear, particularly regarding how molecular-level gene interactions lead to the large-scale patterns observed in embryos. In this study, we present a modeling framework that bridges the gap between molecular gene regulation and tissue-level embryonic patterning. Beginning with basic chemical reaction models of transcription at the single-gene level, we progress to model gene regulatory networks (GRNs) that mediate specific cellular functions. We then introduce phenomenological models of pattern formation, including the French Flag and Temporal Patterning/Speed Regulation models, and integrate them with molecular/GRN realizations. To facilitate understanding and application of our models, we accompany our mathematical framework with computer simulations, providing intuitive and simple code for each model. A key feature of our framework is the explicit articulation of underlying assumptions at each level of the model, from transcriptional regulation to tissue patterning. By making these assumptions clear, we provide a foundation for future experimental and theoretical work to critically examine and challenge them, thereby improving the accuracy and relevance of gene regulatory models in developmental biology. As a case study, we explore how different strategies for integrating enhancer activity affect the robustness and evolvability of GRNs that govern embryonic pattern formation. Our simulations suggest that a two-step regulation strategy, enhancer activation followed by competitive integration at the promoter, ensures more standardized integration of new enhancers into developmental GRNs, highlighting the adaptability of eukaryotic transcription. These findings shed new light on the transcriptional mechanisms underlying embryonic patterning, while the overall modeling framework serves as a foundation for future experimental and theoretical investigations.

Keywords:  development; enhancers; gene regulation; gene regulatory network (GRN); modelling; oscillations; pattern formation; transcription

DOI:  https://doi.org/10.3389/fcell.2025.1522725
Curr Top Dev Biol. 2025 ;pii: S0070-2153(24)00114-5. [Epub ahead of print]162 283-315

Cellular and molecular regulations of oocyte selection and activation in mammals.

Xuebing Yang, Yan Zhang, Hua Zhang.

  Oocytes, a uniquely pivotal cell population, play a central role in species continuity. In mammals, oogenesis involves distinct processes characterized by sequential rounds of selection, arrest, and activation to produce a limited number of mature eggs, fitting their high-survival yet high-cost fertility. During the embryonic phase, oocytes undergo intensive selection via cytoplasmic and organelle enrichment, accompanied by the onset and arrest of meiosis, thereby establishing primordial follicles (PFs) as a finite reproductive reserve. Subsequently, the majority of primary oocytes enter a dormant state and are gradually recruited through a process termed follicle activation, essential for maintaining orderly fertility. Following activation, oocytes undergo rapid growth, experiencing cycles of arrest and activation regulated by endocrine and paracrine signals, ultimately forming fertilizable eggs. Over the past two decades, advancements in genetically modified animal models, high-resolution imaging, and omics technologies have significantly enhanced our understanding of the cellular and molecular mechanisms that govern mammalian oogenesis. These advances offer profound insights into the regulatory mechanisms of mammalian reproduction and associated female infertility disorders. In this chapter, we provide an overview of current knowledge in mammalian oogenesis, with a particular emphasis on oocyte selection and activation in vivo.

Keywords:  Oocyte activation; Oocyte dormancy; Oogenesis; Ovarian reserve; Primordial follicle

DOI:  https://doi.org/10.1016/bs.ctdb.2024.11.003
Curr Top Dev Biol. 2025 ;pii: S0070-2153(24)00108-X. [Epub ahead of print]162 207-258

The mammalian egg's zona pellucida, fertilization, and fertility.

Eveline S Litscher, Paul M Wassarman.

The zona pellucida (ZP) is a relatively thick extracellular matrix (ECM) that surrounds all mammalian eggs and plays vital roles during oogenesis, fertilization, and preimplantation development. The ZP is a semi-permeable, viscous ECM that consists of three or four glycosylated proteins, called ZP1-4, that differ from proteoglycans and proteins of somatic cell ECM. Mammalian ZP proteins are encoded by single-copy genes on different chromosomes and synthesized and secreted by growing oocytes arrested in meiosis. Secreted ZP proteins assemble in the extracellular space into long fibrils that are crosslinked polymers of ZP proteins and exhibit a structural repeat. Several regions of nascent ZP proteins, the signal-sequence, ZP domain, internal and external hydrophobic patches, transmembrane domain, and consensus furin cleavage-site regulate secretion and assembly of the proteins. The ZP domain is required for assembly of ZP fibrils, as well as for assembly of other kinds of ZP domain-containing proteins. ZP proteins adopt immunoglobulin (Ig)-like folds that resemble C- and V-type Ig-like domains, but represent new immunoglobulin-superfamily subtype structures. Interference with synthesis, processing, or secretion of ZP proteins by either gene-targeting in mice or mutations in human ZP genes can result in failure to assemble a ZP and female infertility. ZP2 and ZP3 must be present to assemble a ZP during oocyte growth and both serve as receptors for binding of free-swimming sperm to ovulated eggs. Acrosome-reacted sperm bind to ZP2 polypeptide by inner-acrosomal membrane and acrosome-intact sperm bind to ZP3 oligosaccharides by plasma membrane overlying the sperm head. Binding of acrosome-intact sperm to ZP3 induces them to undergo cellular exocytosis, the acrosome reaction. Only acrosome-reacted sperm can penetrate the ZP, bind to, and then fuse with the egg's plasma membrane to produce a zygote. Following sperm-egg fusion (fertilization) the ZP undergoes structural and functional changes (zona reaction) induced by cortical granule components (cortical reaction) deposited into the ZP. The latter include zinc and ovastacin, a metalloendoprotease that cleaves ZP2 near its amino-terminus and hardens the egg's ZP. The changes prevent penetration of bound sperm through and binding of supernumerary sperm to the ZP of fertilized eggs as part of a secondary or slow block to polyspermy. Therefore, ZP proteins act as structural proteins and sperm receptors, and help to prevent fertilization by more than one sperm. Here we review some of this information and provide details about several key features of ZP proteins, ZP matrix, and mammalian fertilization.

DOI: https://doi.org/10.1016/bs.ctdb.2024.10.008
bioRxiv. 2025 Mar 14. pii: 2025.03.12.642822. [Epub ahead of print]

Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation.

Zihan Meng 姿含孟, Nicholas G Norwitz, Sharon E Bickel.

  Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. Here we show that cohesion maintenance during meiotic prophase in Drosophila oocytes requires the NAD+-dependent deacetylase, Sirt1. Knockdown of Sirt1 during meiotic prophase causes premature loss of arm cohesion and chromosome segregation errors. We have previously demonstrated that when Drosophila oocytes arrest and age in diplotene, segregation errors increase significantly. By quantifying acetylation of the Sirt1 substrate H4K16 on oocytes chromosomes, we find that Sirt1 deacetylase activity declines markedly during aging. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. Our data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors.

Keywords:  Drosophila; SRT1720; maternal age effect; meiosis; sister chromatid cohesion

DOI:  https://doi.org/10.1101/2025.03.12.642822