Anming Meng

Mammalian preimplantation embryos develop more efficiently in groups than in isolation, suggesting that embryos secrete embryotrophic factors that promote development. However, the endogenous embryotrophic signals responsible for this long-recognized phenomenon remain incompletely defined. Using an unbiased proteomic screen for stable maternal proteins that may function as embryonic extracellular signals, we identified the cytokine macrophage migration inhibitory factor (Mif) as an abundant oocyte-stored protein that persists for several days after fertilization in mice. Quantitative measurements of spent culture medium reveal that developing embryos release Mif, with a substantial fraction derived from the maternal deposit. Extracellular Mif levels peak 3–4 days post fertilization, the same period when Mif knockout preimplantation embryos produce its strongest phenotype. Embryos lacking maternal, but not zygotic, Mif display defective blastocyst growth even in group culture. Individually cultured embryos exhibit similar blastocyst growth defects that can be rescued by supplementing recombinant Mif at physiologically relevant concentrations. Mif activates the PI3K-Akt-mTORC1 pathway through the cell-surface receptor Cd74 to promote blastocyst growth and cell proliferation. Together, these findings identify Mif as a potential endogenous contributor to the density-dependent embryotrophic effects and reveal that maternally stored proteins may function long after fertilization as extracellular signaling molecules to support preimplantation development in mammals.

The dorsal organizer, essential for vertebrate embryonic axis formation, is induced by microtubule-mediated transport of maternal determinants. Maternal Huluwa (Hwa) has been identified as an essential organizer inducer in zebrafish and frogs, functioning at midblastula stages to activate β-catenin signaling in the preorganizer. It remains unknown if maternal Hwa functions at or before fertilization. Here, we report that maternal Hwa protein is critical for organizing the vegetal parallel microtubule array immediately after fertilization in zebrafish. Hwa protein and mRNA are enriched at the vegetal pole and facilitate microtubule network formation, enabling asymmetrical transport of dorsal determinants. Loss of maternal Hwa disrupts this microtubule architecture and abrogates mRNA transport, revealing a self-reinforcing mechanism where Hwa regulates its own asymmetrical distribution. Hwa may regulate the vegetal microtubule network through other signaling pathways and microtubule-associated proteins. Our findings establish a dual-phase model of dorsal specification: Hwa initially governs symmetry breaking through postfertilization microtubule organization and later on activates β-catenin signaling at blastula stages. This work provides fundamental insights into how the key maternal factor regulates the organizer and body axis formation at different developmental stages.

Vertebrate heart development requires precise regulation of morphogenetic movements and dysregulation causes congenital heart defects. However, cell polarity remodeling during early heart tube formation remains underexplored. Here, we show that zebrafish ventricular cardiomyocyte precursors (vCPCs) undergo striking polarity reorientation as they transition from a single-layered epithelium to a transient double-layered configuration by involution. During this process, vCPCs remove inner adherens components and re-establish polarity toward the ECM-attached outer surface, enabling proper directional extension to form the ventricle. We identify the junctional scaffold protein Afadin a (Afdna) as a critical regulator. Afdna localizes to the outer and lateral membrane to restrict Rap1 activity, facilitating Podocalyxin translocation and adhesion disassembly at the inner interface between vCPC double layers. afdna mutants exhibit a multilayered ventricle with impaired blood flow, phenocopying human congenital ventricular obliteration. Our findings uncover a polarity-based mechanism ensuring ventricular chamber formation and provide insight into ventricular obliteration.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down’s syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle–Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that ‘aneuploidy predisposition’ constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217

Iron overload induces cellular stress and is implicated in diverse pathological conditions. Nevertheless, the epigenetic mechanisms governing mammalian cellular responses to iron overload remain poorly characterized. Using multi‐omics profiling in human granulosa cells, we show that the transcriptional signature of iron‐stressed granulosa cells recapitulated that of granulosa cells from endometriosis patients. Mechanistically, iron excess triggered a time‐dependent, genome‐wide reduction in chromatin accessibility, which was associated with broad transcriptional suppression. Furthermore, fine‐scale chromatin looping underwent dynamic reorganization, concomitant with dysregulated expression of core iron metabolism genes. We identify SOX4 as a central, dosage‐sensitive regulator of this epigenetic reprogramming: its downregulation under iron stress drives chromatin compaction, while ectopic SOX4 expression largely restores accessibility. Moreover, SOX4 is directly regulated by TFEB through binding to the CLEAR motif in its promoter and, in turn, exerts its function by recruiting the SWI/SNF chromatin remodeling complex. Notably, SOX4 also mediated chromatin compaction under high‐androgen stimulation, suggesting its universal role as a stress‐responsive epigenetic regulator in granulosa cells. These results elucidate a TFEB‐SOX4‐SWI/SNF regulatory axis that orchestrates iron‐responsive chromatin plasticity, and more broadly, uncover SOX4 as a key mediator of chromatin adaptation to pathophysiological stressors, including iron overload and hyperandrogenism.

The coordination of cell migration and proliferation is essential for embryogenesis and tissue homeostasis. However, the classical gradient signaling model is insufficient to explain how stable mitogenic signaling is maintained within migratory cells. Here, we reveal that primordial germ cells (PGCs) in zebrafish employ migrasomes-vesicular organelles formed during migration-to couple their proliferation with migration, ensuring germline expansion. Migrasomes, generated at retraction fibers via tspan7-dependent biogenesis, deliver the growth factor GDF3 specifically to neighboring PGCs through contact-dependent interactions. GDF3 activates the TGF-β receptor acvr1ba, driving proliferation in a spatiotemporally restricted manner. This homocrine signaling mechanism allows migrating PGCs to autonomously sustain proliferation, circumventing signal dilution in embryonic environments. This work uncovers migrasomes as a bridge linking migration and proliferation, with implications for understanding collective cell behaviors in development and disease.

The germ cell fate in zebrafish is determined by germ plasm, whereas mammalian germ cell fate is induced by bone morphogenetic protein (BMP) signaling. It remains elusive whether BMP signaling is implicated in zebrafish germ cell development. Here, we demonstrate that BMP–Smad1/9 signaling plays a critical role in zebrafish primordial germ cell (PGC) maintenance rather than fate determination. BMP inhibition or smad1/9 knockdown reduces PGC numbers. Furthermore, we generated PGC-specific smad1/9 knockouts using a transgenic approach with PGC-specifically expressed Cas9 and ubiquitously expressed guide RNAs. Smad1/9 deficiency in PGCs leads to impaired PGC proliferation and increased apoptosis, consequently reducing PGC numbers. Transcriptome analysis revealed unchanged PGC-specific gene expression, but a marked upregulation of DNA damage response-related genes, which is validated by ectopic ATR–pChk1 activation in PGCs and PGC restoring by ATR inhibition. Collectively, these findings underscore conserved but functionally distinct roles of BMP signaling in vertebrate PGC development.

The dorsal organizer is induced by the maternal factor Huluwa (Hwa) primarily via activation of β-catenin signaling in vertebrate embryos. Although the mitogen-activated protein kinase (MAPK) cascade has been demonstrated to play a role in embryonic development, it remains unclear whether and how the maternal MAPK pathway regulates dorsal organizer formation. Here, we report the implication of maternal Erk1/Erk2 in the dorsal organizer formation of zebrafish embryos. Phosphorylated Erk1/2 (pErk1/2) is enriched in nuclei of presumptive dorsal blastomeres around the 1k-cell stage. Disruption of MAPK/Erk activation by chemical inhibition, maternal transgenic expression of dominant negative Erk2, or genetic mutation of maternal and zygotic erk1/2 genes could impair organizer formation and ventralize some embryos. Conversely, overexpression of the constitutively active form of Erk2 (caErk2) could restore the body axis in Mhwa or Mctnnb2 mutants and even induce two body axes. Mechanistically, Hwa promotes GSK3β degradation and thus stabilizes Ras protein, resulting in elevated pErk1/2 levels during early embryonic development. Intriguingly, maternal Erk1/2 signaling enhances hwa transcription via Jun and Fosab (also named Fos) during oogenesis. Our findings shed new light on the interplay between maternal Erk1/2 signaling and maternal Hwa for the induction of the dorsal organizer and body axis in the zebrafish.

The dorsal organizer, essential for vertebrate embryonic axis formation, is induced by microtubule-mediated transport of maternal determinants. Maternal Huluwa (Hwa) has been identified as an essential organizer inducer in zebrafish and frogs, functioning at midblastula stages to activate β-catenin signaling in the preorganizer. It remains unknown if maternal Hwa functions at or before fertilization. Here, we report that maternal Hwa protein is critical for organizing the vegetal parallel microtubule array immediately after fertilization in zebrafish. Hwa protein and mRNA are enriched at the vegetal pole and facilitate microtubule network formation, enabling asymmetrical transport of dorsal determinants. Loss of maternal Hwa disrupts this microtubule architecture and abrogates mRNA transport, revealing a self-reinforcing mechanism where Hwa regulates its own asymmetrical distribution. Our findings establish a dual-phase model of dorsal specification: Hwa initially governs symmetry breaking through postfertilization microtubule organization and later on activates β-catenin signaling at blastula stages. This work provides fundamental insights into how the key maternal factor regulates the organizer and body axis formation at different developmental stages.