Developmental cellPub Date : 2025-07-02DOI: 10.1016/j.devcel.2025.06.017
Jiejie Yang, Yang Dong, Jiaxin Xu, Xuehong Qian, Yang Cai, Yanjun Chen, Pei Zhang, Ding Gao, Zongqiang Cui, Yixian Cui
{"title":"TM9SF3 is a Golgi-resident ATG8-binding protein essential for Golgi-selective autophagy","authors":"Jiejie Yang, Yang Dong, Jiaxin Xu, Xuehong Qian, Yang Cai, Yanjun Chen, Pei Zhang, Ding Gao, Zongqiang Cui, Yixian Cui","doi":"10.1016/j.devcel.2025.06.017","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.017","url":null,"abstract":"Golgi degradation by selective autophagy (Golgiphagy) requires receptors to direct Golgi fragments into phagophores for sequestration within autophagosomes, followed by lysosomal degradation. Here, we show that the human Golgi transmembrane protein TM9SF3 is a receptor essential for Golgiphagy under nutrient-stress and multiple Golgi-stress conditions. TM9SF3 binds all six mammalian ATG8 proteins through its N-terminal LC3-interacting regions. In U2OS cells, <em>TM9SF3</em> knockout blocks nutrient-stress-induced Golgi fragmentation and reduces the targeting of Golgi fragments to autophagosomes, resulting in decreased Golgi protein degradation. Beyond nutrient stress, TM9SF3 is required for Golgiphagy induced by monensin, brefeldin A, and disruptions in intra-Golgi protein glycosylation. Knockout of <em>TM9SF3</em> and mutations in its LC3-interacting regions (LIRs) both compromise protein glycosylation, whereas <em>TM9SF3</em> overexpression promotes degradation of incompletely glycosylated proteins. Further, we show that TM9SF3 is required for human breast cancer cell proliferation, and high TM9SF3 levels are associated with poor prognosis, implicating its function in breast cancer pathology.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"570 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533893","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}
Developmental cellPub Date : 2025-07-02DOI: 10.1016/j.devcel.2025.06.016
Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C. Vladoiu, Nam Woo Cho, Jacob S. Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A. Suárez, Alexander T. Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Michael D. Taylor
{"title":"Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process","authors":"Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C. Vladoiu, Nam Woo Cho, Jacob S. Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A. Suárez, Alexander T. Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Michael D. Taylor","doi":"10.1016/j.devcel.2025.06.016","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.016","url":null,"abstract":"Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives medulloblastoma leptomeningeal dissemination, whereas premedication with corticosteroids prevents both inflammation and the pro-metastatic effect of radiation. In murine model systems, inflammation in the tumor microenvironment secondary to external beam radiation is both sufficient and necessary to drive leptomeningeal metastases.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"3 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533894","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}
Developmental cellPub Date : 2025-07-02DOI: 10.1016/j.devcel.2025.06.012
Xinyi Yang, Teresa Ferraro, Kelly Molnar, Julien Pontabry, Sam-Rayden Malanda, Nicola Maghelli, Loïc Royer, Stephan W. Grill, Gene Myers, Silvia Grigolon, Michel Labouesse
{"title":"Repeated extrinsic and anisotropic mechanical inputs promote C. elegans polarized adherens junction elongation","authors":"Xinyi Yang, Teresa Ferraro, Kelly Molnar, Julien Pontabry, Sam-Rayden Malanda, Nicola Maghelli, Loïc Royer, Stephan W. Grill, Gene Myers, Silvia Grigolon, Michel Labouesse","doi":"10.1016/j.devcel.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.012","url":null,"abstract":"A key challenge in development is understanding how complex organisms physically coordinate the morphogenesis of multiple tissues. Here, using biophysical approaches, we investigate how muscles under the epidermis specifically stimulate the extension of anterior-posterior (AP)-oriented epidermal adherens junctions during late <em>C. elegans</em> embryonic elongation. First, light-sheet imaging shows that asynchronous patterns of muscle contractions drive embryo rotations. In turn, junctions between the lateral and dorso-ventral epidermis repeatedly oscillate between a folded, hypotensed state and an extended, hypertensed state. Second, fluorescence recovery after photobleaching (FRAP) analysis of an E-cadherin::GFP construct shows that muscle contractions stimulate E-cadherin turnover. Moreover, a mechano-chemical model backed by genetic tests suggests that E-cadherin trafficking controls junction elongation due to lower line tension. Altogether, our results illustrate how muscle contractions fluidize epidermal adherens junctions, which, combined with anisotropic tension in the epidermis, drive their polarized extension.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"6 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533898","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}
Developmental cellPub Date : 2025-07-01DOI: 10.1016/j.devcel.2025.06.013
Shan Lin, Christoph Dieterich, Thiago Britto-Borges, Stefan Günther, Silke Kreher, Yvonne Eibach, Carsten Kuenne, Andre Schneider, Thomas Braun
{"title":"Rbpms2 prevents major cardiac defects in cardiomyocyte-specific Rbpms-deficient mice","authors":"Shan Lin, Christoph Dieterich, Thiago Britto-Borges, Stefan Günther, Silke Kreher, Yvonne Eibach, Carsten Kuenne, Andre Schneider, Thomas Braun","doi":"10.1016/j.devcel.2025.06.013","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.013","url":null,"abstract":"Cell-type-specific splicing depends on RNA-binding splicing factors. Several important splicing factors were identified in cardiomyocytes, including members of the RNA-binding proteins with multiple splicing (RBPMS) family, but their role during heart development has not been fully characterized. Here, we demonstrate that the function of RBPMS overlaps with the closely related paralog RBPMS2. <em>Rbpms</em>-deficient cardiomyocytes exhibit a higher degree of binucleation at birth, but this does not affect heart function in mice substantially until late adulthood. In contrast, <em>Rbpms</em>/<em>Rbpms2</em> (<em>Rbpms/2</em>) compound mutants show pronounced disruption of the splicing network in embryonic cardiomyocytes, which leads to the formation of defective nuclei and disruption of sarcomere structures, eventually resulting in embryonic lethality. We demonstrate that mitotic defects in embryonic <em>Rbpms/2</em>-deficient cardiomyoctes are caused by the disbalance of nuclear and cytoplasmic calcium (Ca<sup>2+</sup>)/CaM-dependent protein kinase II gamma (<em>Camk2g</em>) isoforms. Overexpression of the <em>Rbpmsa</em> isoform partially rescues these defects, preventing embryonic lethality of <em>Rbpms/2</em>-deficient mice, and is sufficient for cardiomyocyte-specific splicing in other cell types.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"152 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520834","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":"Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration","authors":"Junjie Hou, Yabing Song, Chenglu Xiao, Yuanyuan Sun, Jie Shen, Xiaokai Ma, Qinchao Zhou, Shih-Ching Chiu, Yang Xu, Yanyi Huang, Ye-Guang Chen, Xiaojun Zhu, Jianbin Wang, Jing-Wei Xiong","doi":"10.1016/j.devcel.2025.06.015","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.015","url":null,"abstract":"Zebrafish has full capacity of heart regeneration, but little is known about how blood cells, especially platelets, are involved in this regenerative process. Here, we report that <em>cloche/npas4l</em> is a pro-regenerative platelet factor for heart regeneration. We found that haploinsufficiency of <em>npas4l</em> disrupted cardiomyocyte (CM) and endothelial cell (EC) proliferation and heart regeneration after injury. A single-cell transcriptomic atlas identified that <em>npas4l</em> was dynamically expressed in platelets after heart injury and controlled robust interactions between platelet-CMs or -ECs. Decreasing platelets impaired CM/EC proliferation, and overexpression of <em>npas4l</em> in platelets sufficiently induced CM/EC proliferation in uninjured hearts, as well as rescued CM/EC proliferation defects in <em>cloche</em> mutants. Mechanistically, Npas4l positively controlled a panel of ligand expression, including <em>bmp6</em> in platelets, to fine-tune CM proliferation and heart regeneration. Therefore, this work demonstrates platelet Npas4l signaling and presents mechanisms on how platelets modulate CM/EC proliferation via ligand-receptor network during zebrafish heart regeneration.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"9 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520777","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}
Developmental cellPub Date : 2025-06-30DOI: 10.1016/j.devcel.2025.06.007
Robin P. Journot, Mathilde Huyghe, Alexandre Barthelemy, Hugo Couto-Moreira, Tom Deshayes, Louise Harari, Jakub Sumbal, Marisa M. Faraldo, Maxime Dubail, Charles Fouillade, Silvia Fre
{"title":"Conserved signals control self-organization and symmetry breaking of murine bilayered epithelia during development and regeneration","authors":"Robin P. Journot, Mathilde Huyghe, Alexandre Barthelemy, Hugo Couto-Moreira, Tom Deshayes, Louise Harari, Jakub Sumbal, Marisa M. Faraldo, Maxime Dubail, Charles Fouillade, Silvia Fre","doi":"10.1016/j.devcel.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.007","url":null,"abstract":"Organ development relies on molecular cues that guide stem cells to differentiate within precise spatial arrangements. After injury, restoring these patterns is key for regeneration. Yet, how tissue geometry shapes cell fate remains unclear. This study employs a comprehensive approach using <em>in vitro</em> organoids, <em>ex vivo</em> embryonic tissue explants, and single-cell quantitative imaging to investigate cell fate acquisition in four murine bilayered epithelia during development and regeneration. The findings identify that tissue architecture serves as the primary driver of cell fate decisions, with symmetry breaking initiated during early cell internalization. Genetic and pharmacological analyses demonstrate that Hippo/YAP and Notch signaling pathways coordinate to link tissue structure with differentiation outcomes. This study identifies the inherent capacity of stem cells to self-organize into multicellular structures, where the precise position of each differentiated cell is critical to instruct their differentiation choices during embryonic development and regeneration.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"104 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516211","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}
Developmental cellPub Date : 2025-06-30DOI: 10.1016/j.devcel.2025.06.008
Yoshiaki Nosaka, Masahiro Nagano, Yukihiro Yabuta, Baku Nakakita, So I. Nagaoka, Ikuhiro Okamoto, Hiromichi Sasada, Ken Mizuta, Fumiya Umemura, Hiroto Kuma, Yasushi Okochi, Yoshitaka Katou, Bernard de Massy, Azusa Inoue, Akihito Horie, Masaki Mandai, Hiroshi Ohta, Mitinori Saitou
{"title":"Generation of germinal-vesicle oocytes from mouse embryonic stem cells under an ovarian soma-free condition","authors":"Yoshiaki Nosaka, Masahiro Nagano, Yukihiro Yabuta, Baku Nakakita, So I. Nagaoka, Ikuhiro Okamoto, Hiromichi Sasada, Ken Mizuta, Fumiya Umemura, Hiroto Kuma, Yasushi Okochi, Yoshitaka Katou, Bernard de Massy, Azusa Inoue, Akihito Horie, Masaki Mandai, Hiroshi Ohta, Mitinori Saitou","doi":"10.1016/j.devcel.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.008","url":null,"abstract":"<em>In vitro</em> oogenesis provides a platform to elucidate the mechanisms of oocyte development and advance reproductive medicine. The prevalent <em>in vitro</em> oogenesis model requires ovarian somatic cells (OSCs) to support oocyte development; yet, complex three-dimensional oocyte-OSC interactions pose difficulties in systems regulation and mechanistic understanding. Here, we present an OSC-free system of <em>in vitro</em> oogenesis: upon optimized provision of retinoic acid and bone morphogenetic protein on feeders, mouse primordial germ-cell-like cells induced from embryonic stem cells propagate robustly, and enter/progress through meiotic prophase I, generating abundant fetal oocyte-like cells at diplotene arrest. With key cytokines, signaling activators, and antioxidants, they show prominent growth and differentiate into cells comparable to germinal-vesicle oocytes in morphology, transcriptome, and histone modification profiles, with competence to resume meiosis with germinal-vesicle breakdown. By reconstituting major phases of oogenesis with minimal components, our study creates a foundation for OSC-free <em>in vitro</em> oogenesis in mammals, including humans.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"63 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516347","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}
Developmental cellPub Date : 2025-06-27DOI: 10.1016/j.devcel.2025.06.006
Irène Amblard, Damir Baranasic, Sheila Q. Xie, Benjamin Moyon, Michelle Percharde, Boris Lenhard, Vicki Metzis
{"title":"A dual enhancer-attenuator element ensures transient Cdx2 expression during mouse posterior body formation","authors":"Irène Amblard, Damir Baranasic, Sheila Q. Xie, Benjamin Moyon, Michelle Percharde, Boris Lenhard, Vicki Metzis","doi":"10.1016/j.devcel.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.006","url":null,"abstract":"During development, cells express precise gene expression programs to assemble the trunk of the body plan. Appropriate control over the duration of the transcription factor <ce:italic>Cdx2</ce:italic> is critical to achieve this outcome, yet how cells control the onset, maintenance, or termination of <ce:italic>Cdx2</ce:italic> has remained unclear. Here, we delineate the <ce:italic>cis</ce:italic>-regulatory logic orchestrating dynamic <ce:italic>Cdx2</ce:italic> expression in mouse caudal epiblast progenitors and their derivatives. Combining CRISPR-mediated deletion of regulatory elements with <ce:italic>in vitro</ce:italic> models and <ce:italic>in vivo</ce:italic> validation, we demonstrate that distinct enhancers and a repressive element embedded at the <ce:italic>Cdx2</ce:italic> locus act sequentially to drive transient <ce:italic>Cdx2</ce:italic> expression. We pinpoint an “attenuator”: a minimal region relying on a nuclear receptor to extinguish <ce:italic>Cdx2</ce:italic>. Changing this single motif converts the attenuator to an enhancer with the opposite regulatory behavior. Our findings establish a dual <ce:italic>cis</ce:italic>-regulatory logic ensuring precise spatiotemporal control over gene expression for vertebrate body patterning.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"92 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503827","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}
Developmental cellPub Date : 2025-06-26DOI: 10.1016/j.devcel.2025.06.005
Adam Varady, Sarah Grissenberger, Kristin Fischer, Manuela Theresa Stadler, Andrea Wenninger-Weinzierl, Marcus Strobl, Nina Zila, Heinrich Kovar, Martin Distel
{"title":"zHORSE as an optogenetic zebrafish strain for precise spatiotemporal control over gene expression during development","authors":"Adam Varady, Sarah Grissenberger, Kristin Fischer, Manuela Theresa Stadler, Andrea Wenninger-Weinzierl, Marcus Strobl, Nina Zila, Heinrich Kovar, Martin Distel","doi":"10.1016/j.devcel.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.005","url":null,"abstract":"Proper vertebrate development is dependent on tightly regulated expression of genes at the correct time and place. To identify normal but also dysregulated development leading to disease, <em>in vivo</em> interrogation methods with high spatiotemporal resolution are required. Recently, optogenetic tools to manipulate gene expression with spatiotemporal control have emerged, but their <em>in vivo</em> applications remain challenging. Here, we present a transgenic zebrafish strain termed zebrafish for heat-shock-inducible optogenetic recombinase expression (zHORSE) with inducible expression of a light-activatable Cre recombinase. We demonstrate that zHORSE endows robust spatiotemporal control over gene expression down to single-cell level at different developmental stages. We apply zHORSE for lineage tracing to identify caudal fin progenitors and for targeted expression of oncogenes. Surprisingly, one oncogene, EWS::FLI1, can cause ectopic fin formation when induced in permissive environments. zHORSE is compatible with existing <em>loxP</em> zebrafish effector strains and will enable many applications ranging from dissecting and precisely manipulating development to clonal cancer modeling.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"26 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488426","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}
Developmental cellPub Date : 2025-06-25DOI: 10.1016/j.devcel.2025.06.004
Anzy Miller, Veronica Biga, Andrew Rowntree, Mariya Chhatriwala, Florence Woods, Benjamin Noble, Elli Marinopoulou, Anoushka Kamath, Ludovic Vallier, Nancy Papalopulu
{"title":"NGN3 oscillatory expression controls the timing of human pancreatic endocrine differentiation","authors":"Anzy Miller, Veronica Biga, Andrew Rowntree, Mariya Chhatriwala, Florence Woods, Benjamin Noble, Elli Marinopoulou, Anoushka Kamath, Ludovic Vallier, Nancy Papalopulu","doi":"10.1016/j.devcel.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.004","url":null,"abstract":"Understanding protein expression dynamics is crucial for the mechanistic understanding of cell differentiation. We investigate the dynamics and decoding of NEUROGENIN3 (NGN3), a transcription factor critical for pancreatic endocrine development. A knockin endogenous reporter shows that NGN3 protein oscillates with a 13-h periodicity in human induced pluripotent stem cell (hiPSC)-derived endocrine progenitors and is switched off as cells differentiate to β-like and pre-α cells. Increasing NGN3 protein stability results in one broad peak of expression instead of oscillations, with a larger peak-to-trough fold-change. This leads to precocious endocrine differentiation and earlier expression of key NGN3 target genes. Single-cell analysis of dynamics, mathematical modeling, and experimental validation suggest that NGN3 oscillations are decoded by fold-change detection (FCD) rather than the level of expression via an incoherent feedforward loop (IFFL) motif that explains both normal and precocious differentiation. Our findings suggest that oscillatory NGN3 dynamics control the timing of differentiation but not fate specification.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"20 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479505","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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