Genes & development最新文献

{"title":"MEIOSIN retains a STRA8-independent activity that contributes to meiotic gene activation across vertebrates.","authors":"Ryuki Shimada, Yukiko Imai, Kimi Araki, Toshihiro Kawasaki, Sakie Iisaka, Shingo Usuki, Kei-Ichiro Yasunaga, Sayoko Fujimura, Naoki Tani, Hitoshi Niwa, Shigehiro Kuraku, Noriyoshi Sakai, Kei-Ichiro Ishiguro","doi":"10.1101/gad.353802.126","DOIUrl":"10.1101/gad.353802.126","url":null,"abstract":"<p><p>Meiotic entry in vertebrates has been viewed as a transcriptional switch driven by the MEIOSIN-STRA8 axis, but whether this represents the ancestral regulatory logic of meiosis has remained unclear. Here we combine comparative genomics with genetic and single-cell analyses in zebrafish and mice to show that MEIOSIN retains an intrinsic STRA8-independent activity. We identify <i>Meiosin</i> orthologs in zebrafish and hagfish, vertebrate lineages that lack Stra8, and show that these proteins retain the HMG domain but have lost the bHLH domain required for the canonical MEIOSIN-STRA8 interaction. In zebrafish, <i>meiosin</i> is transiently induced at meiotic entry in both sexes, yet its loss selectively disrupts the female germline, causing failure of oogenesis and female-to-male sex reversal. In mice, MEIOSIN lacking the bHLH domain still initiates key features of meiotic entry and partially activates meiotic target genes, although it fails to support full meiotic progression. Together, these findings support a model in which HMG-containing MEIOSIN provides a conserved core activity for meiotic gene activation, whereas STRA8 and the bHLH-mediated MEIOSIN-STRA8 interaction reinforce the efficiency and robustness of this program in lineages that retain the canonical module.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1629-1648"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimerization of ELAV in <i>Drosophila</i> is essential for directing neuronal alternative splicing and polyadenylation programs.","authors":"Thomas C Dix, David W J McQuarrie, Ulrike Bräuer, Yuan W Tian, Irmgard U Haussmann, Min Li, Klaus Fütterer, Matthias Soller","doi":"10.1101/gad.353688.126","DOIUrl":"10.1101/gad.353688.126","url":null,"abstract":"<p><p>ELAV/Hu RNA-binding proteins (RBPs) are key regulators of neuronal alternative splicing and polyadenylation programs across animals. How ELAV/Hu RBPs achieve gene-specific regulation by recognizing spaced U-rich motifs through multimerization, remains uncertain. We determined X-ray crystal structures of ELAV RNA recognition motif 3 (RRM3) to reveal that multimerization is mediated by two evolutionarily conserved interfaces in non-RNA-binding parts of the RRM to form a tetramer and RNA binding is not required for multimerization. Mutational probing of these two interfaces in <i>Drosophila</i> photoreceptor neurons shows that both interfaces contribute to ELAV function in development. Notably, multimerization defective <i>Drosophila elav</i> mutants are embryonic lethal. Genomic profiling demonstrates that multimerization is required to direct neuronal alternative splicing and polyadenylation programs of some, but not all ELAV target genes. Our study provides a structural basis for a mechanistic understanding how ELAV/Hu proteins can extract gene-specific regulation from a landscape of redundant sequence motifs.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1669-1687"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Honeybadger, a micropeptide encoded by an alternative <i>PVT1</i> transcript, is a critical negative regulator of RAS-MAPK signaling in MYC-driven tumors.","authors":"Utkarsha Paithane, Ashutosh Tiwari, Bryan Hall, Kojiro Tashiro, Olivier Saulnier, Quang Trinh, Aditi Soni, Takuma Nakashima, Andrey A Bobkov, Lynn Miya Fujimoto, Mayank Saraswat, Shahab Sarmashghi, Liam D Hendrikse, Meher Beigi Masihi, Shrawantee Saha, Srija Ghosh, Brian James, Anders Erickson, Tanja Eisemann, Theophilos Tzaridis, Badrinath Konety, Scott M Dehm, Rameen Beroukhim, Lukas Chavez, David A Largaespada, Lincoln Stein, Hiromichi Suzuki, William A Weiss, Johannes Yeh, Jianhua Zhao, Robert J Wechsler-Reya, Michael D Taylor, Anindya Bagchi","doi":"10.1101/gad.353356.125","DOIUrl":"10.1101/gad.353356.125","url":null,"abstract":"<p><p>Genomic rearrangements can drive cancer through mechanisms that extend beyond classical oncogenic fusions such as <i>BCR-ABL</i> A substantial fraction of these events involve long noncoding RNAs (lncRNAs), yet their functional impact on tumorigenesis has remained largely opaque. The lncRNA <i>plasmacytoma variant translocation 1</i> (<i>PVT1</i>), positioned adjacent to <i>MYC</i> at chromosome 8q24, is among the most frequently altered loci in MYC-driven (MYC⁺) cancers. We recently showed that <i>PVT1</i> translocations produce a characteristic asymmetric architecture that preserves the 5'-<i>PVT1</i> region, generating a circular RNA (<i>CircPVT1</i>) that encodes Firefox (FFX), a novel oncoprotein that activates AKT-mTORC1 signaling and cooperates with MYC. Here, we uncover a complementary and opposing function for the deleted 3'-<i>PVT1</i> segment, which encodes a tumor-suppressive micropeptide we term Honeybadger (HNB). HNB binds KRAS and dampens RAS-MAPK signaling, and its loss derepresses this pathway and stabilizes MYC via Ser⁶² phosphorylation. Thus, a single class of structural alterations at <i>PVT1</i> simultaneously installs FFX-mediated AKT-mTORC1 activation and removes HNB-mediated RAS-MAPK regulation, creating a dual mechanism that synergistically amplifies MYC output. This oncoprotein gain coupled with tumor-suppressor loss provides a mechanistic explanation for the particularly poor prognosis of <i>PVT1</i>-rearranged cancers and establishes <i>PVT1</i> as a central regulatory hub in MYC⁺ malignancies.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1706-1723"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148791669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Firefox, a protein encoded by circular <i>PVT1</i>, is essential for MYC-driven oncogenesis.","authors":"Ashutosh Tiwari, Utkarsha Paithane, Kojiro Tashiro, Bryan Hall, Jordan Friedlein, Mayank Saraswat, Olivier Saulnier, Karina Barbosa, Quang Trinh, Shrawantee Saha, Aditi Soni, Takuma Nakashima, Rabi Murad, Svetlana Maurya, Owen S Chapman, Brian James, Anders Erickson, Joshua T Lange, Robyn Leary, Jyotika Varshney, Badrinath Konety, Scott M Dehm, Yasuhiko Kawakami, David A Largaespada, William A Weiss, Lincoln Stein, Lukas Chavez, Hiromichi Suzuki, Sihan Wu, Jianhua Zhao, Aniruddha J Deshpande, Michael D Taylor, Robert J Wechsler-Reya, Anindya Bagchi","doi":"10.1101/gad.353355.125","DOIUrl":"10.1101/gad.353355.125","url":null,"abstract":"<p><p>MYC-driven (MYC⁺) cancers are highly aggressive and often fatal. MYC dysregulation is a key event in these cancers, yet MYC overexpression alone is often insufficient to initiate or sustain tumorigenesis. <i>Plasmocytoma variant translocation 1</i> (<i>PVT1</i>), a long noncoding RNA (lncRNA) adjacent to <i>MYC</i> on chromosome 8q24, is frequently co-amplified with <i>MYC</i> in many of these cancers. Our prior work showed that <i>PVT1</i> potentiates MYC function, although the underlying mechanism has remained unclear. Here we show that, in addition to amplification with <i>MYC</i>, genomic rearrangements at <i>PVT1</i> frequently involve unbalanced translocations that asymmetrically enrich 5'-<i>PVT1</i> while depleting 3'-<i>PVT1</i> The retained 5'-<i>PVT1</i> region generates a circular RNA, <i>CircPVT1</i>, that encodes a novel protein we have named Firefox (FFX). We show that FFX is essential for MYC-mediated oncogenic signaling, as its depletion markedly reduces MYC protein abundance and transcriptional output. Mechanistically, FFX stimulates AKT-mTORC1 signaling and enhances cap-dependent translational and biosynthetic capacity, thereby establishing a self-reinforcing oncogenic circuit that amplifies MYC activity. Inducible depletion of FFX in vivo significantly impairs tumor growth in MYC⁺ xenograft models. These findings define FFX as a critical effector within the <i>MYC</i>-<i>PVT1</i> locus and reveal a therapeutically actionable vulnerability in MYC⁺ cancers.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1688-1705"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148791649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.","authors":"Caleb Cheng, Rüya Pakkan, Arul M Chinnaiyan, Costas A Lyssiotis","doi":"10.1101/gad.353702.126","DOIUrl":"10.1101/gad.353702.126","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor-host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1578-1597"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initial perturbations triggered by p53 loss in stem cells","authors":"Yang Fan,Amanda E. Jones,Yulei Wei,Yi Ding,Chendong Yang,Ralph J. DeBerardinis,Jun Wu,John M. Abrams","doi":"10.1101/gad.353794.126","DOIUrl":"https://doi.org/10.1101/gad.353794.126","url":null,"abstract":"p53 is frequently mutated in human cancers, but how it normally acts to prevent transformation is not fully understood. The initial events triggered by p53 loss are commonly extrapolated from cell lines, patient tumors, or mouse models in which p53 has been absent for long durations (e.g., months, years). In these contexts, collateral changes, competitive selection, and secondary adaptations may obscure the immediate impact of p53 elimination. Therefore, to inspect the direct consequences triggered by p53 loss in real time, we developed a platform that enables conditional removal of p53 in unstressed mouse embryonic stem cells. Within 48 h, activated germline programs were accompanied by altered chromatin profiles and downregulated canonical p53 targets. At the single-cell level, extensive heterogeneity was observed in the form of erupting retroelements, increased SINE accessibility, features of Warburg metabolism, and functional germ cell effectors (e.g., Dmrt1 and PGC7/Dppa3 ). Together, these findings expose ground state functions for p53 and establish that germline transitions, activated mobile elements, and metabolic reprogramming define acute perturbations caused by p53 loss.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"51 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Drosophila</i> Scm self-assembles into PcG bodies to recruit PRC2.1 to target genes during Polycomb silencing initiation.","authors":"David B Lyons, Corbin J Arbizzani, Oguz Kanca, Steven Z DeLuca","doi":"10.1101/gad.353999.126","DOIUrl":"https://doi.org/10.1101/gad.353999.126","url":null,"abstract":"<p><p>While Polycomb-based gene silencing relies upon the generation of large, condensed domains of histone H3K27 trimethylation, the mechanisms forming and maintaining these domains are incompletely understood. Several previously identified mechanisms concentrate PRC2 and its H3K27me3 activity, including allosteric activation, binding to H2Aub, and concentration into PcG bodies through weak multivalent interactions with other Polycomb group proteins. Here, using the <i>Drosophila</i> nurse cell system to study silencing initiation in developing tissue, we discover a new mechanism. The scaffolding protein Sex comb on midleg (Scm) first polymerizes into PcG bodies independently of PRC1 and PRC2. These Scm-containing bodies then recruit PRC2 through a direct, structured interaction between the Scm-Zf-FCS domain and the Pcl atypical Tudor domain. Finally, we show that the Scm-Zf-FCS/Pcl-Tudor interaction is required for viability and Hox gene regulation during somatic cell development. Our work discovers a new mechanism anchoring PRC2 to PcG bodies that explains how cells can rapidly create and maintain large domains of H3K27me3. It also raises a new possibility that cells could regulate Scm polymerization to determine the size and location of H3K27me3 domains.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic imprinting of the metabolic regulator gene <i>Klf14</i> is regulated by a paternal sub-TAD anchored at <i>Mest</i>.","authors":"Amanda Ha, Natsuki Hayashi, Aaron B Bogutz, Benoit Moindrot, Laura Gomez, Juliette Harris, Alexandre Marcil, Frank Court, Miyuki Shindo, Philippe Arnaud, Jacques Drouin, Thierry Forné, Daan Noordermeer, Shuji Takada, Kazuhiko Nakabayashi, Louis Lefebvre","doi":"10.1101/gad.353948.126","DOIUrl":"https://doi.org/10.1101/gad.353948.126","url":null,"abstract":"<p><p>KLF14 acts as a master regulator of gene expression in adipose tissue and variants at the human <i>KLF14</i> gene show reproducible association with type 2 diabetes and metabolic syndrome. Risk alleles are only pathological when maternally inherited, consistent with the observation that <i>KLF14/Klf14</i> is a maternally expressed imprinted gene in human and mouse. However, how genomic imprinting is regulated at this important locus is currently unknown. In both species, <i>KLF14/Klf14</i> is located ∼200 kb away from the paternally expressed imprinted gene <i>MEST/Mest</i>, regulated by a maternal gametic differentially methylated region (gDMR) at its promoter. Although the <i>Klf14</i> promoter is unmethylated in most tissues, maternally inherited DNA methylation marks are paradoxically required for <i>Klf14</i> expression. Here, we show that <i>Mest</i> and <i>Klf14</i> reside within the same topologically associating domain (TAD) in embryonic stem cells (ESCs), defined by biallelic CTCF binding at the boundaries. Using allele-specific 4C-seq, we show that CTCF binding to the unmethylated <i>Mest</i> gDMR generates a paternal allele-specific sub-TAD encompassing <i>Klf14</i> CRISPR-Cas9 deletions of the paternal <i>Mest</i> promoter region in ESCs and in vivo in mutant mice result in loss of <i>Mest</i> expression and acquisition of biallelic expression at <i>Klf14</i> By analyzing epigenetic marks and chromatin looping in <i>Klf14</i>-expressing pituitary cells, we identify a putative enhancer element shared by <i>Mest</i> and <i>Klf14</i>, providing a mechanistic model for the regulation of <i>Klf14</i> imprinting. This work defines a new role for the <i>Mest</i> maternally methylated gDMR, revealing that it exerts long-range effects via allele-specific modulation of TAD structures and acts as an imprinting control region in the regulation of <i>Klf14</i> imprinting.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.","authors":"Yeon J Lee, Koning Shen, Andrew Dillin, Donald C Rio","doi":"10.1101/gad.353720.126","DOIUrl":"https://doi.org/10.1101/gad.353720.126","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss and has been genetically linked to mutations in RNA-binding proteins. A mutation D262V in the RNA-binding protein hnRNPA1, found in a subset of ALS patients, causes widespread splicing pattern changes. Cells expressing this hnRNPA1 mutation exhibit aggregation, reduced proliferation, altered stress granules and abnormal neuronal growth. To further elucidate how a single amino acid substitution in a splicing factor might impact cell growth, we employed ribosome profiling to study translational dynamics across the transcriptome in hnRNPA1 mutant cells. Differential ribosome occupancy was observed for a small number of transcripts linked to synaptic organization and GTPase functions, as well as disrupted codon usage and a global stalling of translation. This downregulation of translation coincided with suppression of the mTOR/AKT signaling pathway. RNA splicing changes in transcripts from genes linked to cilia/cell projections, GTPase cycles and glutamate signaling were also observed. Importantly, major mitochondrial dysfunction and mitochondrial fragmentation were found in hnRNPA1 D262V mutant cells. Overall, this study demonstrates how a single amino acid change in an RNA binding protein can contribute to disrupting cell growth and mitochondrial function related to defects linked to neuronal death in ALS.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymphatics-epicardial cross talk via Reelin controls cardiac growth","authors":"Yalu Zhou,Sara Pascual El Bobakry,Arpita Roy,Carlos Torroja,Tatjana Dorn,Sophie Zengerle,Olivia Vidal-Cruchez,Saman Kahn,Xiaoyan Liang,Susan E. Quaggin,Alessandra Moretti,Issam Ben-Sahra,Benjamin R. Thomson,Beatriz Sosa-Pineda,Guillermo Oliver","doi":"10.1101/gad.354151.126","DOIUrl":"https://doi.org/10.1101/gad.354151.126","url":null,"abstract":"How mammalian organ size is precisely regulated remains incompletely understood. This process depends on the coordinated balance between cell proliferation, differentiation, and apoptosis. In the heart, the epicardium plays a central role in embryonic cardiac growth as a source of multiple cardiac progenitor lineages. The transcription factor Wt1 is essential for epicardial development and maturation, and its loss disrupts epicardial maintenance and the generation of epicardial-derived cells (EPDCs). In addition, the epicardium produces mitogenic factors required for cardiomyocyte (CM) proliferation, including those of the insulin-like growth factor ( IGF ) signaling pathway. Consistently, functional inactivation of Igf1 or Igf2 in mice results in severe prenatal growth reduction, with mutant embryos ∼60% smaller than controls, underscoring the roles of these genes in organ and fetal growth. We recently identified the cardiac lymphatic vasculature as an unexpected regulator of heart size during embryonic development. Here, by combining single-cell RNA sequencing with loss-of-function mouse models, we uncover a critical regulatory network linking cardiac lymphatics, the epicardium, Wt1 , and Igf1 signaling that controls the final stages of embryonic cardiac growth. Our findings suggest that cardiac lymphatics act as a physiological quality control system for heart growth. Furthermore, using gain-of-function approaches in human epicardial organoids, we demonstrate that Reelin promotes epicardial fate, suggesting that the beneficial roles of lymphatics in adult cardiac repair are likely mediated through Reelin-dependent epicardial reactivation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"40 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148932601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}