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The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription

Nature Communications 2025年第1期16卷 1-19页

作者： Umphred-Wilson, Katharine Ratnayake, Shashikala Tang, Qianzi Wang, Rui Chaudhary, Sneha Ghosh Ballachanda, Devaiah N. Trichka, Josephine Wisniewski, Jan Zhou, Lan Chen, Qingrong Meerzaman, Daoud Singer, Dinah S. Adoro, Stanley Experimental Immunology Branch National Cancer Institute National Institutes of Health Bethesda 20892 MD United States Immunology Training Program Department of Pathology Case Western Reserve University School of Medicine Cleveland 44106 OH United States Computational Genomics and Bioinformatics Branch Center for Biomedical Informatics & Information Technology National Cancer Institute National Institutes of Health Bethesda 20850 MD United States College of Animal Science and Technology Sichuan Agricultural University Chengdu 611130 China Department of Pathology and Genomic Medicine Houston Methodist Hospital Houston 77030 TX United States

Addiction to oncogene-rewired transcriptional networks is a therapeutic vulnerability in cancer cells, underscoring a need to better understand mechanisms that relay oncogene signals to the transcriptional machinery. Here, using human and mouse T cell acute lymphoblastic leukemia (T-ALL) models, we identify an essential requirement for the endosomal sorting complex required for transport protein CHMP5 in T-ALL epigenetic and transcriptional programming. CHMP5 is highly expressed in T-ALL cells where it mediates recruitment of the coactivator BRD4 and the histone acetyl transferase p300 to enhancers and super-enhancers that enable transcription of T-ALL genes. Consequently, CHMP5 depletion causes severe downregulation of critical T-ALL genes, mitigates chemoresistance and impairs T-ALL initiation by oncogenic NOTCH1 in vivo. Altogether, our findings uncover a non-oncogene dependency on CHMP5 that enables T-ALL initiation and maintenance. © This is a U.S. Government work and not under copyright protection in the US;foreign copyright protection may apply 2025.

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Human endogenous retroviruses (HERVs) associated with glioblastoma risk and prognosis

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Cancer Gene Therapy 2025年 1-11页

作者： Mazumder, Harun Lin, Hui-Yi Baddoo, Melody Gałan, Wojciech Polania-Villanueva, Diana Hicks, Chindo Otohinoyi, David Peruzzi, Francesca Madeja, Zbigniew Belancio, Victoria P. Flemington, Erik K. Reiss, Krzysztof Rak, Monika Biostatistics Program Louisiana State University Health Sciences Center School of Public Health New Orleans LA United States Louisiana Cancer Research Center New Orleans LA United States Tulane Cancer Center Tulane Health Sciences Center New Orleans LA United States Stanley S. Scott Cancer Center Louisiana State University Health Sciences Center New Orleans LA United States Department of Genetics and the Bioinformatics and Genomics Program Louisiana State University Health Sciences Center School of Medicine New Orleans LA United States Department of Medicine Louisiana State University Health Sciences Center School of Medicine New Orleans LA United States Department of Cell Biology Jagiellonian University in Kraków Faculty of Biochemistry Biophysics and Biotechnology Kraków Poland Department of Structural and Cellular Biology Tulane University School of Medicine New Orleans LA United States Department of Pathology and Laboratory Medicine Tulane University School of Medicine New Orleans LA United States Department of Interdisciplinary Oncology Louisiana State University Health Sciences Center School of Medicine New Orleans LA United States

Emerging evidence suggests expression from human endogenous retrovirus (HERV) loci likely contributes to, or is a biomarker of, glioblastoma multiforme (GBM) disease progression. However, the relationship between HERV expression and GBM malignant phenotype is unclear. Applying several in silico analyses based on data from The Cancer Genome Atlas (TCGA), we derived a locus-specific HERV transcriptome for glioma that revealed 211 HERVs significantly dysregulated in the comparisons of GBM vs. normal brain (NB), GBM vs. low-grade glioma (LGG), and LGG vs. NB. Our analysis supported development of a unique HERV scoring algorithm that segregated GBM, LGG, and NB. Interestingly, lower HERV scores showed correlation with lower survival in GBM. However, HERV scores were less robust in predicting LGG survival or LGG progression to GBM. Functional prediction analysis linked the 211 HERV loci with 18 voltage-gated potassium channel genes. The functional link between dysregulated HERVs and specific potassium channel genes may contribute to better understanding of GBM pathogenesis, disease progression, and possibly drug resistance. © The Author(s) 2025.

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Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy

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Redox Biology 2025年 84卷 103676页

作者： Kourakis, Stephanie Timpani, Cara A. Bagaric, Ryan M. Qi, Bo Ali, Benazir A. Boyer, Rebecca Spiesberger, Guinevere Kandhari, Nitika Yan, Xu Kuang, Jujiao Tulangekar, Ankita de Haan, Judy B. Deveson-Lucas, Deanna Stupka, Nicole Fischer, Dirk Rybalka, Emma Institute for Health and Sport (IHeS) Victoria University Melbourne VIC Australia Inherited and Acquired Myopathies Program Australian Institute for Musculoskeletal Science (AIMSS) St Albans VIC Australia Department of Medicine – Western Health Melbourne Medical School The University of Melbourne St Albans VIC Australia Monash Genomics and Bioinformatics Platform Biomedical Discovery Institute Monash University Clayton VIC Australia Sarcopenia Research Program Australian Institute for Musculoskeletal Science (AIMSS) St Albans VIC Australia Basic Science Domain Oxidative Stress Laboratory Baker Heart and Diabetes Institute Melbourne VIC Australia Baker Department of Cardiometabolic Health University of Melbourne Parkville VIC Australia Division of Neuropediatric and Developmental Medicine University Children's Hospital of Basel (UKBB) Basel Switzerland

In inherited neuromuscular disease, Duchenne muscular dystrophy (DMD), glucocorticoids significantly slow disease progression yet impart side effects severe enough to preclude use in a significant proportion of patients. Extending our findings that acute treatment with FDA approved multiple sclerosis drug, dimethyl fumarate (DMF), rescues muscle pathology in juvenile mdx mice, we aimed to conduct tiered pre-clinical testing toward translation. To aggravate disease phenotype in adult mdx muscles that usually lack human equivalent muscle pathology, we used bi-weekly treadmill running for 4 weeks which increased plasma DMD biomarker, creatine kinase, by 2-fold and quadriceps fibrosis by ∼30 %. Using this model, we screened DMF for 5 weeks in a head-to-head comparison, and in combination, with standard-of-care prednisone (PRED), to model the most likely clinical trial scenario. We show comparable efficacy between DMF and PRED at reducing inflammation via NF-κB suppression and CD68⁺ macrophage infiltration. Moderate term DMF monotherapy had additional anti-fibrotic and anti-lipogenic effects on skeletal and cardiac muscle beyond those seen with PRED treatment, although combination therapy exacerbated fibrosis in quadriceps. Our study supports DMF as a repurposing candidate for DMD, especially for patients who cannot tolerate chronic glucocorticoid treatment. We also highlight the importance of evaluating combination therapy to identify potential off-target effects between emerging therapeutics and glucocorticoids towards better designed clinical trials. © 2025

关键词： Dimethyl fumarate Duchenne muscular dystrophy Muscle pathology Therapeutics

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Spliceosomal genes in the *** genome:a comparison with those in ***,***,*** and ***

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Protein & Cell 2011年第5期2卷 395-409页

作者： Bing Yu Petra Fey Karen E.Kestin-Pilcher Alexei Fedorov Ashwin Prakash Rex L.Chisholm Jane Y.Wu Department of Molecular and Clinical Genetics Royal Prince Alfred Hospital and Sydney Medical School(Central)the University of SydneyNSW 2006Australia dictyBase Center for Genetic MedicineNorthwestern UniversityChicagoIL 60611USA Department of Neurology and Lurie Comprehensive Cancer Center Center for Genetic MedicineNorthwestern University Feinberg Medical SchoolChicagoIL 60611USA Department of Medicine and Program in Bioinformatics and Proteomics/Genomics The University of ToledoToledoOH 43614USA

Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely *** analysis suggests that pre-mRNA splicing plays an important role in *** gene expression as two thirds of its genes contain at least one *** curation of the genome to date has revealed 40 genes in *** with clear evidence of alternative splicing,supporting the existence of alternative splicing in this unicellular *** identified 160 candidate U2-type spliceosomal proteins and related factors in *** based on 264 known human genes involved in *** small ribonucleoproteins(snRNPs),PRP19 complex proteins and late-acting proteins are highly conserved in *** and throughout the *** non-snRNP and hnRNP families,*** orthologs are closer to those in ***,*** and *** than to their counterparts in *** splicing regulators,including SR proteins and CUGbinding proteins,were found in ***,but not in *** comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in *** where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.

关键词： pre-mRNA splicing spliceosomal genes Dictyostelium discoideum comparative genomics splicing regulators

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Protecting centrosomes from fracturing enables efficient cell navigation

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Science Advances 2025年第17期11卷

作者： Schmitt, Madeleine T. Kroll, Janina Ruiz-Fernandez, Mauricio J.A. Hauschild, Robert Ghosh, Shaunak Kameritsch, Petra Merrin, Jack Schmid, Johanna Stefanowski, Kasia Thomae, Andreas W. Cheng, Jingyuan Öztan, Gamze Naz Konopka, Peter Ortega, Germán Camargo Penz, Thomas Bach, Luisa Baumjohann, Dirk Bock, Christoph Straub, Tobias Meissner, Felix Kiermaier, Eva Renkawitz, Jörg Biomedical Center Walter Brendel Center of Experimental Medicine Institute of Cardiovascular Physiology and Pathophysiology Klinikum der Universität Ludwig Maximilians Universität München Munich Germany Institute of Science and Technology Austria Klosterneuburg Austria Institute Immune and Tumor Biology University of Bonn Bonn Germany Bioimaging Facility Biomedical Center Faculty of Medicine Ludwig Maximilians Universität München Munich Germany Institute of Innate Immunity Department of Systems Immunology and Proteomics Medical Faculty University of Bonn Bonn Germany Institute of Stem Cell Research Helmholtz Center Munich German Research Center for Environmental Health Munich Germany Physiological Genomics Biomedical Center Ludwig-Maximilians University Munich Germany CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria Medical Clinic III for Oncology Hematology Immuno-Oncology and Rheumatology University Hospital Bonn University of Bonn Bonn Germany Medical University of Vienna Institute of Artificial Intelligence Center for Medical Data Science Vienna Austria Bioinformatics Unit Biomedical Center Faculty of Medicine Ludwig Maximilians Universität München Munich Germany

The centrosome is a microtubule orchestrator, nucleating and anchoring microtubules that grow radially and exert forces on cargos. At the same time, mechanical stresses from the microenvironment and cellular shape changes compress and bend microtubules. Yet, centrosomes are membraneless organelles, raising the question of how centrosomes withstand mechanical forces. Here, we discover that centrosomes can deform and even fracture. We reveal that centrosomes experience deformations during navigational pathfinding within motile cells. Coherence of the centrosome is maintained by Dyrk3 and cNAP1, preventing fracturing by forces. While cells can compensate for the depletion of centriolar-based centrosomes, the fracturing of centrosomes impedes cellular function by generating coexisting microtubule organizing centers that compete during path navigation and thereby cause cellular entanglement in the microenvironment. Our findings show that cells actively maintain the integrity of the centrosome to withstand mechanical forces. These results suggest that centrosome stability preservation is fundamental, given that almost all cells in multicellular organisms experience forces. © 2025 The Authors, some rights reserved;exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

关键词： Cell culture

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Double negative T cells,a potential biomarker for systemic lupus erythematosus

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Precision Clinical medicine 2020年第1期3卷 34-43页

作者： Jessy J.Alexander Alexander Jacob Anthony Chang Richard J.Quigg James N.Jarvis Department of Pathology University of ChicagoChicagoIL 60637USA Departments of Medicine PediatricsJacobs School of Medicine and Biomedical Sciences and GeneticsGenomics&Bioinformatics ProgramUniversity at BuffaloBuffaloNY 14203USA

Systemic lupus erythematosus(SLE)is an autoimmune disease that is a challenge to diagnose and *** is an urgent need for biomarkers to help define organ involvement,and more effective therapies.A unique population of T cells,the CD3^(+)CD4^(−)CD8^(−)(DNeg)cells,is significantly increased in lupus *** cases(53%)of pediatric SLE patients had elevated DNeg cells in their peripheral blood,which correlated with kidney function(R^(2)=0.54).Significant infiltration of DNeg cells was observed in both adult and pediatric lupus kidneys by *** the first time,this study provides direct evidence that DNeg cells facilitate kidney injury in preclinical 8-week-old MRL/lpr lupus *** lupus mice,the increase in DNeg cells tracked with worsening disease and correlated with kidney function(R^(2)=0.85).Our results show that DNeg cells per se can cause kidney dysfunction,increase in number with increase in disease pathology,and could serve as a potential biomarker.

关键词： CD3^(+)CD4^(−)CD8^(−)T cells glomerulonephritis inflammation lupus

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Long-term PM2.5 exposure is associated with asthma prevalence and exhaled nitric oxide levels in children

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Pediatric research 2025年第1期97卷 370-377页

作者： Yi-Giien Tsai Chia-Pin Chio Kuender D Yang Ching-Hsiung Lin Yen-Po Yeh Yu-Jun Chang Jien-Wen Chien Shu-Li Wang Shau-Ku Huang Chang-Chuan Chan Department of Pediatrics Changhua Christian Children's Hospital Changhua Taiwan ROC. School of Medicine Kaohsiung Medical University Kaohsiung Taiwan ROC. School of Medicine Chung Shan Medical University Taichung Taiwan ROC. Department of Post-Baccalaureate Medicine College of Medicine National Chung Hsing University Taichung Taiwan ROC. Department of Medical Research Tungs' Taichung MetroHarbor Hospital Taichung Taiwan ROC. Institute of Environmental and Occupational Health Sciences College of Public Health National Taiwan University Taipei Taiwan ROC. Department of Pediatrics Mackay Memorial Hospital and Department of Microbiology & Immunology National Defense Medical Center Taipei Taiwan ROC. Division of Chest Medicine Department of Internal Medicine Changhua Christian Hospital Changhua Taiwan ROC. Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan ROC. Ph.D. Program in Translational Medicine National Chung Hsing University Taichung Taiwan ROC. Department of Recreation and Holistic Wellness MingDao University Changhua Taiwan ROC. Changhua County Public Health Bureau Changhua Taiwan ROC. Epidemiology and Biostatistics Center Changhua Christian Hospital Changhua Taiwan ROC. National Institute of Environmental Health Sciences National Health Research Institutes 35 Keyan Rd Zhunan Miaoli County Miaoli Taiwan ROC. slwang@nhri.edu.tw. National Institute of Environmental Health Sciences National Health Research Institutes 35 Keyan Rd Zhunan Miaoli County Miaoli Taiwan ROC. skhuang@nhri.edu.tw. Johns Hopkins Asthma and Allergy Center School of Medicine Johns Hopkins University Baltimore MD USA. skhuang@nhri.edu.tw. Institute of Environmental and Occupational Health Sciences College of Public Health National Taiwan University Taipei Taiwan ROC. ccchan@ntu.edu.tw.

BACKGROUND:Exhaled nitric oxide concentration (FENO) is a marker of airway inflammation. This study aimed to evaluate the association of air pollution exposure with FENO levels and asthma prevalence with respiratory symptoms in school children. METHODS:We analyzed 4736 school children who reside in six townships near industrial areas in central Taiwan. We evaluated asthmatic symptoms, FENO, and conducted the environmental questionnaire. The personal exposure of PM, NO, and SO was estimated using land-use regression models data on children's school and home addresses. RESULTS:Annual exposure to PM was associated with increased odds of physician-diagnosed asthma (OR = 1.595), exercise-induced wheezing (OR = 1.726), itchy eyes (OR = 1.417), and current nasal problems (OR = 1.334) (P < 0.05). FENO levels in the absence of infection were positively correlated with age, previous wheezing, allergic rhinitis, atopic eczema, near the road, and for children with high exposure to PM (P < 0.05). An increase of 1 μg/m PM exposure was significantly associated with a 1.0% increase in FENO levels for children after adjusting for potential confounding variables, including exposures to NO and SO. CONCLUSIONS:Long-term exposures to PM posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children. IMPACT:Annual exposure to PM was associated with increased odds of physician-diagnosed asthma and nasal problems and itchy eyes. Long-term exposures to PM2.5 were significantly associated with FENO levels after adjusting for potential confounding variables. This is first study to assess the association between FENO levels and long-term air pollution exposures in children near coal-based power plants. An increase of 1 μg/m annual PM exposure was significantly associated with a 1.0% increase in FENO levels. Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of chil

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From mechanism to medicine: The progress and potential of epigenetics in osteoarthritis

Osteoarthritis and Cartilage Open

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Osteoarthritis and Cartilage Open 2025年第3期7卷 100621-100621页

作者： Roberts, Jack B. Rockel, Jason S. Mulders, Rick Capellini, Terence D. Appleton, C. Thomas Phanstiel, Douglas H. Lories, Rik Geurts, Jeroen Ali, Shabana Amanda Bhutani, Nidhi Stone, Laura Cruz-Almeida, Yenisel Jurisica, Igor Boer, Cindy G. Ramos, Yolande F.M. Rice, Sarah J. Kapoor, Mohit Biosciences Institute Newcastle University Newcastle upon Tyne United Kingdom Division of Orthopedics Osteoarthritis Research Program Schroeder Arthritis Institute University Health Network and Krembil Research Institute University Health Network Toronto ON Canada Department of Medical Biophysics and Computer Science University of Toronto Toronto ON Canada Department of Biomedical Data Sciences Section Molecular Epidemiology Leiden University Medical Center Leiden Netherlands Department of Human Evolutionary Biology Harvard University Cambridge MA United States Bone and Joint Institute and Department of Medicine Schulich School of Medicine and Dentistry Western University London Canada Curriculum in Bioinformatics and Computational Biology University of North Carolina Chapel Hill NC United States Laboratory of Tissue Homeostasis and Disease Skeletal Biology and Engineering Research Centre Department of Development and Regeneration KU Leuven Leuven Belgium Division of Rheumatology University Hospitals Leuven Leuven Belgium Rheumatology Department of Musculoskeletal Medicine Lausanne University Hospital and University of Lausanne (CHUV-UNIL) Lausanne Switzerland Bone and Joint Center Henry Ford Health + Michigan State University Health Sciences Detroit MI United States Department of Orthopaedic Surgery Stanford School of Medicine Stanford CA United States Department of Anesthesiology School of Medicine University of Minnesota Minneapolis MN United States Pain Research and Intervention Center of Excellence (PRICE) at the University of Florida Gainesville FL United States Department of Internal Medicine Genomics Medicine Center Erasmus MC University Medical Center Rotterdam Netherlands Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada Department of Surgery University of Toronto Toronto ON Canada

Objective: Osteoarthritis (OA) is a chronic, degenerative disease of the articular joints. The disease presents an enormous clinical and economic burden globally, due in part to the lack of disease modifying therapies. For over a decade, OA researchers have been working to determine epigenetic mechanisms underlying the disease to better understand pathology, identify biomarkers of progression, and pinpoint novel targets for therapeutic intervention. Design: This article presents a summary of the 3rd International Workshop on the Epigenetics of Osteoarthritis held in Toronto, Ontario, Canada, in September 2024. The purpose of this meeting was to gather the international community to discuss the status of OA epigenetic research and share expertise on innovative techniques for future. Results: Since the two previous meetings, there has been increasing adoption of advanced single-cell and spatial sequencing technologies and bioinfomatic analyses. Furthermore, investigations of multiple joint tissues has highlighted the shifting paradigm from OA as a cartilage centric disease to the consideration of all joint tissues. Conclusions: The workshop provided a unique opportunity for early-career researchers to expand their network, and for all participants to discuss new or improved approaches to advance the field, including international consortia and data sharing. The highlights and outcomes from this OA epigenetics workshop are described in this report. © 2025 The Authors

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Revelation of potential antiviral activity of Azadirachta indica against Zika virus protease: An integrated molecular docking and dynamic simulation approach

Computational and Structural Biotechnology Reports

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Computational and Structural Biotechnology Reports 2025年 2卷

作者： Md. Habib Ullah Masum Rehana Parvin Syed Mohammad Lokman Zarin Tasnim Md. Mazharul Alam Jannatul Ferdous Department of Genomics and Bioinformatics Faculty of Biotechnology and Genetic Engineering Chattogram Veterinary and Animal Sciences University Khulshi 4225 Bangladesh Department of Pathology and Parasitology Faculty of Veterinary Medicine Chattogram Veterinary and Animal Sciences University Khulshi 4225 Bangladesh Asian University for Women (AUW) Chattogram 4000 Bangladesh Department of Industrial Biotechnology Faculty of Biotechnology and Genetic Engineering Chattogram Veterinary and Animal Sciences University Khulshi 4225 Bangladesh Functional Genomics and Proteomics Laboratory (FGPL) Department of Genetic Engineering and Biotechnology Faculty of Biological Sciences University of Chittagong Chattogram 4331 Bangladesh Department of Obstetrics and Gynecology Chittagong Medical College Hospital Chattogram 4203 Bangladesh

The Zika virus (ZIKV) is an RNA virus that mostly affects humans and primates and is transmitted via Aedes mosquitoes . The emergence of ZIKV has intensified global health concerns, emphasizing the urgent need for effective antiviral therapies. As a vital enzyme in the replication of ZIKV, the NS2B-NS3 protease offers a promising therapeutic target. This study leverages computer-aided drug design to identify bioactive compounds capable of inhibiting the ZIKV NS2B-NS3 protease, thereby disrupting viral replication. Bioactive compounds from Azadirachta indica were screened through virtual approaches, resulting in six with exceptional docking scores (<-5.5 kcal/mol). Analyses of the physicochemical properties validated the drug-like traits of the IMPHY014854 and IMPHY014908, conveying suitable hydrogen bonding profiles and moderate solubility (Log S: −2.22 to −3.60). Evaluations of pharmacokinetics suggested significant gastrointestinal absorption while exposing no permeability across the blood-brain barrier, thereby reducing interactions with the central nervous system. Toxicity evaluations revealed limited toxic effects, while several bioactive compounds exhibited particular toxicological issues. Molecular dynamics simulations further revealed the stability and interaction dynamics of ZIKV protease-ligand complexes, where the IMPHY014854 and IMPHY014908 exhibited significant residue flexibility, compactness, and solvent accessibility profiles over a 100 ns simulation. Principal component analysis revealed conformational distinctions, while Gibbs's free energy analysis demonstrated greater stability for the ZIKV protease-IMPHY014908 complex. This integrative computational strategy highlights the potential of phytochemicals as the ZIKV protease inhibitors and provides a foundation for developing effective antiviral drugs. Further, in vivo studies must be implemented to validate these findings and advance therapeutic prospects against ZIKV.

关键词： Mosquito-borne Phytodynamics Biocomputational Neem plant Protease inhibitor Antiviral drug

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Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development

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Nature Neuroscience 2025年 1-14页

作者： Ya’el Courtney Joshua P. Head Neil Dani Frederick B. Shipley Maria K. Lehtinen Olga V. Chechneva Cameron Sadegh Yong Zhang Michael J. Holtzman Towia A. Libermann Department of Pathology Boston Children’s Hospital and Harvard Medical School Boston MA USA Graduate Program in Neuroscience Harvard Medical School Boston MA USA Department of Cell and Developmental Biology Vanderbilt University Nashville TN USA Graduate Program in Biophysics Harvard University Cambridge MA USA Department of Neurosurgery University of California Davis Sacramento CA USA Pulmonary and Critical Care Medicine Department of Medicine Washington University School of Medicine St. Louis MO USA Proteomics Bioinformatics and Systems Biology Center Beth Israel Deaconess Medical Center and Harvard Medical School Boston MA USA

The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of serotonergic 5-HT2Creceptors (by WAY-161503) triggers sustained Ca2+signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors lining the brain’s ventricles and shifting their developmental trajectory. Inducing ChP secretion in utero in mice disrupts neural progenitor dynamics, cerebral cortical architecture and offspring behavior. Additionally, illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in the mouse embryo. Our findings reveal a fundamental secretory pathway in the ChP that shapes brain development, highlighting how its disruption can have lasting consequences for brain health.

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