Pub Date : 2026-01-14Epub Date: 2025-09-10DOI: 10.1016/j.devcel.2025.08.012
Philippe Petry, Alexander Oschwald, Simon Merkt, Thien-Ly Julia Dinh, Geoffroy Andrieux, Cylia Crisand, Hannah Botterer, Elisa Nent, Neil Paterson, Monique Havermans, Roman Sankowski, Oliver Schilling, Melanie Boerries, Lukas Amann, Olaf Groß, Andreas Schlitzer, Marco Prinz, Tim Lämmermann, Katrin Kierdorf
Macrophage progenitors colonize their anatomical niches in the central nervous system (CNS) in distinct pre- and postnatal waves. Microglia progenitors originate from early erythromyeloid progenitors in the yolk sac and enter the murine CNS around embryonic day (E)9.5. While their developmental origin is well established, the molecular mechanisms guiding CNS colonization are not yet resolved. Using transcriptomic and proteomic approaches, we identified potential factors involved in this process. Microglia progenitors showed a distinct integrin surface profile and transmigrate along the extracellular matrix (ECM)-enriched pial surface into the CNS, pointing to a mesenchyme-to-CNS migration route. Loss of the integrin adaptor protein talin-1 in microglia progenitors led to a reduced CNS colonization, whereas macrophage progenitors in the surrounding mesenchyme remained unchanged. Overall, our data suggest that microglial progenitors enter the CNS parenchyma via talin-1-mediated migration from the surrounding mesenchyme through the ECM-enriched pial surface.
{"title":"Early microglia progenitors colonize the embryonic CNS via integrin-mediated migration from the pial surface.","authors":"Philippe Petry, Alexander Oschwald, Simon Merkt, Thien-Ly Julia Dinh, Geoffroy Andrieux, Cylia Crisand, Hannah Botterer, Elisa Nent, Neil Paterson, Monique Havermans, Roman Sankowski, Oliver Schilling, Melanie Boerries, Lukas Amann, Olaf Groß, Andreas Schlitzer, Marco Prinz, Tim Lämmermann, Katrin Kierdorf","doi":"10.1016/j.devcel.2025.08.012","DOIUrl":"10.1016/j.devcel.2025.08.012","url":null,"abstract":"<p><p>Macrophage progenitors colonize their anatomical niches in the central nervous system (CNS) in distinct pre- and postnatal waves. Microglia progenitors originate from early erythromyeloid progenitors in the yolk sac and enter the murine CNS around embryonic day (E)9.5. While their developmental origin is well established, the molecular mechanisms guiding CNS colonization are not yet resolved. Using transcriptomic and proteomic approaches, we identified potential factors involved in this process. Microglia progenitors showed a distinct integrin surface profile and transmigrate along the extracellular matrix (ECM)-enriched pial surface into the CNS, pointing to a mesenchyme-to-CNS migration route. Loss of the integrin adaptor protein talin-1 in microglia progenitors led to a reduced CNS colonization, whereas macrophage progenitors in the surrounding mesenchyme remained unchanged. Overall, our data suggest that microglial progenitors enter the CNS parenchyma via talin-1-mediated migration from the surrounding mesenchyme through the ECM-enriched pial surface.</p>","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":" ","pages":"85-101.e7"},"PeriodicalIF":8.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039301","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}
Pub Date : 2026-01-14DOI: 10.1016/j.devcel.2025.12.005
Irma Tkachenko, Christian Luschnig
Two recent studies reveal that TMK receptor kinases directly phosphorylate and stabilize PIN auxin exporters in plants, forming rapid feedback loops that reinforce directional auxin flow. Together, these papers uncover a unifying mechanism in which auxin perception at the plasma membrane instructs PIN polarity, transport efficiency, and self-organizing growth behavior.
{"title":"When auxin meets its master: TMKs orchestrate self-organizing growth in plants.","authors":"Irma Tkachenko, Christian Luschnig","doi":"10.1016/j.devcel.2025.12.005","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.12.005","url":null,"abstract":"<p><p>Two recent studies reveal that TMK receptor kinases directly phosphorylate and stabilize PIN auxin exporters in plants, forming rapid feedback loops that reinforce directional auxin flow. Together, these papers uncover a unifying mechanism in which auxin perception at the plasma membrane instructs PIN polarity, transport efficiency, and self-organizing growth behavior.</p>","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"61 1","pages":"5-6"},"PeriodicalIF":8.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988733","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}
Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human pluripotent stem cell (hPSC)-based prefrontal cortex (PFC) platform, we examined three high-confidence environmental and genetic factors associated with depression: chronic exposure to high levels of cortisol or interferon alpha (IFN-a), and a mutation in SIRTUIN 1 (SIRT1). All three conditions induced overlapping phenotypes of neuronal dysfunction, characterized by dendritic atrophy, synaptic loss, and neuronal hypoactivity across multiple cell lines. RNA sequencing uncovered converging alterations in neuronal cholesterol homeostasis. Depleting cholesterol in control neurons reproduced core depression-associated neuronal phenotypes, while cholesterol supplementation was sufficient to rescue these phenotypes in depression-associated conditions. These findings point to cholesterol imbalance as a common driver of neuronal dysfunction in MDD, linking diverse genetic and environmental risk factors through a shared cellular pathway.
{"title":"Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis.","authors":"Polina Oberst, Nan Xu, Hermany Munguba, Chao Zhang, Aaron Zhong, Ting Zhou, Conor Liston, Joshua Levitz, Lorenz Studer","doi":"10.1016/j.devcel.2025.08.011","DOIUrl":"10.1016/j.devcel.2025.08.011","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human pluripotent stem cell (hPSC)-based prefrontal cortex (PFC) platform, we examined three high-confidence environmental and genetic factors associated with depression: chronic exposure to high levels of cortisol or interferon alpha (IFN-a), and a mutation in SIRTUIN 1 (SIRT1). All three conditions induced overlapping phenotypes of neuronal dysfunction, characterized by dendritic atrophy, synaptic loss, and neuronal hypoactivity across multiple cell lines. RNA sequencing uncovered converging alterations in neuronal cholesterol homeostasis. Depleting cholesterol in control neurons reproduced core depression-associated neuronal phenotypes, while cholesterol supplementation was sufficient to rescue these phenotypes in depression-associated conditions. These findings point to cholesterol imbalance as a common driver of neuronal dysfunction in MDD, linking diverse genetic and environmental risk factors through a shared cellular pathway.</p>","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":" ","pages":"102-116.e6"},"PeriodicalIF":8.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039281","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}
Stimulator of interferon (IFN) genes (STING, also known as [mediator of IRF3 activation]) is a 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) receptor that activates type I IFN responses to inhibit tumorigenesis in tumor cells. However, STING agonists show limited antitumor clinical efficacy. Here, we demonstrate that STING in macrophages promotes the survival of regulatory T cells (Tregs) and the progression of non-small cell lung cancer (NSCLC) in KRasG12D autochthonous NSCLC mouse models. Mechanistically, STING-mediated nuclear factor κB (NF-κB) activation upregulates CD38 in Siglec-Flow macrophages to hydrolyze extracellular nicotinamide adenine dinucleotide (NAD) in the tumor microenvironment (TME). Genetic deletion of STING or CD38, or pharmacological CD38 inhibition, restores NAD levels, triggers Treg apoptosis through the ART2-P2RX7 axis, and enhances antitumor CD8+ T cell responses. Importantly, CD38 inhibition improves the efficacy of low-dose anti-CTLA4 therapy. These findings uncover a previously uncharacterized cGAMP-STING-CD38 axis in macrophages supporting Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers.
{"title":"MITA/STING-driven CD38 induction in Siglec-Flow macrophages promotes regulatory T cell survival and non-small cell lung cancer progression","authors":"Zhi-Dong Zhang, Yu-Lin Lin, Han-Yue Zhang, Cong Zuo, Zhong-Lin Zhu, Xing-Yuan Wang, Hao-Yu Duan, Junjie Zhang, Dandan Lin, Bo Zhong","doi":"10.1016/j.devcel.2025.12.007","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.12.007","url":null,"abstract":"Stimulator of interferon (IFN) genes (STING, also known as [mediator of IRF3 activation]) is a 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) receptor that activates type I IFN responses to inhibit tumorigenesis in tumor cells. However, STING agonists show limited antitumor clinical efficacy. Here, we demonstrate that STING in macrophages promotes the survival of regulatory T cells (Tregs) and the progression of non-small cell lung cancer (NSCLC) in KRas<sup>G12D</sup> autochthonous NSCLC mouse models. Mechanistically, STING-mediated nuclear factor κB (NF-κB) activation upregulates CD38 in Siglec-F<sup>low</sup> macrophages to hydrolyze extracellular nicotinamide adenine dinucleotide (NAD) in the tumor microenvironment (TME). Genetic deletion of STING or CD38, or pharmacological CD38 inhibition, restores NAD levels, triggers Treg apoptosis through the ART2-P2RX7 axis, and enhances antitumor CD8<sup>+</sup> T cell responses. Importantly, CD38 inhibition improves the efficacy of low-dose anti-CTLA4 therapy. These findings uncover a previously uncharacterized cGAMP-STING-CD38 axis in macrophages supporting Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"52 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961686","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}
Pub Date : 2026-01-12DOI: 10.1016/j.devcel.2025.12.009
Yusong Lyu, Kun Wu, Yang Zhou, Jiahong Du, Chuanjia Liu, Yan Wang, Qingbo Yuan, Xinli Dong, Zheyuan Hong, Muhammad Fahad, Yuxin Shen, Fuxi Rong, Xiangdong Fu, Peisong Hu, Liang Wu
High nitrogen (HN) fertilizer routinely enhances crop yields, but it often leads to undesirable late flowering and delayed maturation compared with moderate nitrogen (MN). Here, we identify FLOWERING LOCUS T 4 (FT4) in monocots, which functions as an anti-florigen and regulates flowering time responsive to HN availability. Molecular study reveals that FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) forms nuclear condensates to promote FT4 degradation with the assistance of scaffold protein GIGANTEA (GI) in model grass Brachypodium distachyon, ensuring the timely flowering under MN conditions. However, HN regime impairs the liquid-liquid phase separation capacity of BdFKF1 and disrupts its binding to GI, thereby stabilizing BdFT4 and delaying flowering. In rice, natural variations within the intrinsically disordered region of OsFKF1 contribute to flowering adaptive to varying soil N levels across different geographical regions. These results hold a potential for improving agricultural sustainability through modulation of the FKF1-FT4 regulon in monocot crops.
{"title":"FKF1 nuclear condensates control anti-florigen turnover and flowering onset in response to nitrogen availability in monocots","authors":"Yusong Lyu, Kun Wu, Yang Zhou, Jiahong Du, Chuanjia Liu, Yan Wang, Qingbo Yuan, Xinli Dong, Zheyuan Hong, Muhammad Fahad, Yuxin Shen, Fuxi Rong, Xiangdong Fu, Peisong Hu, Liang Wu","doi":"10.1016/j.devcel.2025.12.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.12.009","url":null,"abstract":"High nitrogen (HN) fertilizer routinely enhances crop yields, but it often leads to undesirable late flowering and delayed maturation compared with moderate nitrogen (MN). Here, we identify FLOWERING LOCUS T 4 (FT4) in monocots, which functions as an anti-florigen and regulates flowering time responsive to HN availability. Molecular study reveals that FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) forms nuclear condensates to promote FT4 degradation with the assistance of scaffold protein GIGANTEA (GI) in model grass Brachypodium distachyon, ensuring the timely flowering under MN conditions. However, HN regime impairs the liquid-liquid phase separation capacity of BdFKF1 and disrupts its binding to GI, thereby stabilizing BdFT4 and delaying flowering. In rice, natural variations within the intrinsically disordered region of OsFKF1 contribute to flowering adaptive to varying soil N levels across different geographical regions. These results hold a potential for improving agricultural sustainability through modulation of the FKF1-FT4 regulon in monocot crops.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"52 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961696","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}
Pub Date : 2026-01-05DOI: 10.1016/j.devcel.2025.12.003
Man Wang, Yi Chen, Ming Guo, Pengzhi Xie, Xinzhe Zhao, Shulin Chen, Yian Deng, Rui Hu, Qianyi Wan, Juanyu Zhou, Zhuzhen Zhang, Ke Lan, Haiyang Chen, Yuan Liu
Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a critical role for impaired intestinal epithelial repair in the local intestinal etiology of long COVID. Mechanistically, we show that intestinal SARS-CoV-2 reservoirs disrupt very-long-chain fatty acid (VLCFA) metabolism, suppressing activation of peroxisome proliferator-activated receptor (PPAR) signaling and reducing peroxisome abundance. This disruption impairs intestinal stem cell differentiation and epithelial regeneration, resulting in prolonged GI symptoms including diarrhea, inflammation, and microbiota dysbiosis. Importantly, the FDA-approved sodium phenylbutyrate (NaPB) and fenofibrate alleviate these symptoms by promoting peroxisome proliferation and restoring epithelial repair. These findings provide insights into the GI pathogenesis of long COVID and highlight the therapeutic potential of enhancing the VLCFA-PPAR-peroxisome axis to mitigate persistent GI complications.
{"title":"Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID","authors":"Man Wang, Yi Chen, Ming Guo, Pengzhi Xie, Xinzhe Zhao, Shulin Chen, Yian Deng, Rui Hu, Qianyi Wan, Juanyu Zhou, Zhuzhen Zhang, Ke Lan, Haiyang Chen, Yuan Liu","doi":"10.1016/j.devcel.2025.12.003","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.12.003","url":null,"abstract":"Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a critical role for impaired intestinal epithelial repair in the local intestinal etiology of long COVID. Mechanistically, we show that intestinal SARS-CoV-2 reservoirs disrupt very-long-chain fatty acid (VLCFA) metabolism, suppressing activation of peroxisome proliferator-activated receptor (PPAR) signaling and reducing peroxisome abundance. This disruption impairs intestinal stem cell differentiation and epithelial regeneration, resulting in prolonged GI symptoms including diarrhea, inflammation, and microbiota dysbiosis. Importantly, the FDA-approved sodium phenylbutyrate (NaPB) and fenofibrate alleviate these symptoms by promoting peroxisome proliferation and restoring epithelial repair. These findings provide insights into the GI pathogenesis of long COVID and highlight the therapeutic potential of enhancing the VLCFA-PPAR-peroxisome axis to mitigate persistent GI complications.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"34 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897790","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}
Organoids, 3D in vitro structures derived from embryonic or adult stem cells, offer powerful models for studying tissue patterning, development, morphogenesis, organ physiology, and disease. These systems replicate biological processes, such as cell differentiation, symmetry breaking, and tissue organization, while revealing species-specific developmental variations. Biophysical factors, such as extracellular matrix composition, cell motility, tissue flows, and stiffness, interact with biochemical signals to drive organoid formation, revealing complex multiscale phenomenon during growth, patterning, and homeostasis. Physics-based approaches provide a framework to understand these processes from first principles. In recent years, a growing community of researchers has been exploring what can be termed the “biophysics of organoids.” This review covers a broad range of approaches—mechanical, kinetic, information-based, statistical, and artificial intelligence (AI)-driven—to study organoid development, offering insights into organogenesis, disease modeling, and regenerative medicine.
{"title":"Biophysics of organoids","authors":"Vanessa Weichselberger, Gareth Moore, Sham Tlili, Matthias Merkel, Pierre-François Lenne, Vikas Trivedi","doi":"10.1016/j.devcel.2025.11.008","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.11.008","url":null,"abstract":"Organoids, 3D <em>in vitro</em> structures derived from embryonic or adult stem cells, offer powerful models for studying tissue patterning, development, morphogenesis, organ physiology, and disease. These systems replicate biological processes, such as cell differentiation, symmetry breaking, and tissue organization, while revealing species-specific developmental variations. Biophysical factors, such as extracellular matrix composition, cell motility, tissue flows, and stiffness, interact with biochemical signals to drive organoid formation, revealing complex multiscale phenomenon during growth, patterning, and homeostasis. Physics-based approaches provide a framework to understand these processes from first principles. In recent years, a growing community of researchers has been exploring what can be termed the “biophysics of organoids.” This review covers a broad range of approaches—mechanical, kinetic, information-based, statistical, and artificial intelligence (AI)-driven—to study organoid development, offering insights into organogenesis, disease modeling, and regenerative medicine.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"20 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801495","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}
Pub Date : 2025-12-15DOI: 10.1016/j.devcel.2025.11.006
Hanwen Yu, Yan Liu
How do ci-regulatory differences, across mouse subspecies and over evolutionary timescales, shape cell-type specification and maturation during corticogenesis? In this issue of Developmental Cell, Medina-Cano et al. establish a scalable mouse organoid platform that recapitulates developmental dynamics and enables mapping of allele-specific expression, linking cis-regulatory variation with neurodevelopmental mechanisms and disease-associated genetics.
{"title":"Generating 3D mouse organoids for cortex development and evo-devo.","authors":"Hanwen Yu, Yan Liu","doi":"10.1016/j.devcel.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.11.006","url":null,"abstract":"<p><p>How do ci-regulatory differences, across mouse subspecies and over evolutionary timescales, shape cell-type specification and maturation during corticogenesis? In this issue of Developmental Cell, Medina-Cano et al. establish a scalable mouse organoid platform that recapitulates developmental dynamics and enables mapping of allele-specific expression, linking cis-regulatory variation with neurodevelopmental mechanisms and disease-associated genetics.</p>","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"60 24","pages":"3361-3363"},"PeriodicalIF":8.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767426","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}
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