Biology subjects

Jin, Z.

Publications and source records attributed to Jin, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

A novel proliferative candidate genes panel for idiopathic pulmonary fibrosis: insights from integrated bulk and single-cell RNA sequencing

BackgroundIdiopathic pulmonary fibrosis (IPF) remains a fatal interstitial lung disease with limited diagnostic specificity and therapeutic options. This study integrates bulk and single-cell RNA sequencing (RNA-seq) to identify novel biomarkers and elucidate molecular mechanisms underlying IPF pathogenesis. MethodsWe prospectively enrolled 14 treatment-naive IPF patients and 6 controls. Bulk RNA-seq was performed on bronchoalveolar lavage fluid (BALF), while single-cell RNA-seq analyzed lung tissues from 4 IPF patients and 3 controls. Differentially expressed genes (DEGs) were identified (|log2FC| >1, FDR <0.05), followed by functional enrichment, protein-protein interaction (PPI) network analysis, and cell-type-specific expression profiling. Results1. DEG Identification: Bulk RNA-seq revealed 108 DEGs (24 upregulated, 84 downregulated). KEGG enrichment analysis of DEGs revealed that upregulated genes were mainly enriched in inflammation and immune pathways (such as NF-{kappa}B signaling pathway, Fc epsilon RI signaling pathway, B cell receptor signaling pathway, phagosome, Fc gamma R-mediated phagocytosis), pyrimidine metabolism, cell cycle, and PI3K-Akt signaling pathway. 2. PPI Network: Module analysis identified a proliferative gene module 1 (NUF2, CEP55, ANLN, TTK, TK1, MYBL2, CCNA2, RRM2, CDT1) linked to cell division and cycle regulation. 3. Single-Cell Insights: scRNA-seq of 30,477 cells delineated 11 populations. Module 1 genes exhibited predominant expression in proliferating cells, Module 1 signature score of proliferating cells was significantly higher in IPF than in control group. 4. Pathogenic Links: Key genes (e.g., CEP55, TTK) were associated with PI3K/AKT signaling, epithelial-mesenchymal transition (EMT), and anti-apoptotic pathways, mirroring oncogenic mechanisms. ConclusionThis multi-omics approach uncovers a proliferation-centric gene module in IPF, revealing shared molecular pathways with tumorigenesis. Our findings highlight novel diagnostic biomarkers and suggest repurposing cell cycle inhibitors as potential therapies. Future studies should validate these targets in preclinical models to advance precision medicine for IPF.

genetics↗

bioRxiv2026

Integrated inference of cancer gene expression from cell-free plasma chromatin

Gene expression is a defining determinant of tumor identity, behavior, and therapeutic response, yet remains challenging to measure noninvasively. Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on [~]270,000 gene-sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on >15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred NECTIN4 expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.

genomics↗

bioRxiv2026

Brainwide dopamine dynamics across sleep-wake transitions

Dopaminergic signaling plays a critical role in regulating arousal and transitions between sleep states, yet brainwide dynamics underlying these transitions remain incompletely characterized. Here, we employed multi-site fiber photometry with the dopamine sensor GRAB-DA2m, combined with electroencephalogram (EEG)/electromyogram (EMG) recordings, to systematically assess regional dopamine (DA) dynamics across sleep-wake states in the medial prefrontal cortex (mPFC), striatal subregions, central amygdala (CeA), and midbrain nuclei in mice. We found that DA levels prominently increased in the mPFC, dorsolateral striatum (DLS), ventral tegmental area (VTA), substantia nigra pars compacta (SNc), and dorsal raphe nucleus (DRN) during transitions from non-rapid eye movement (NREM) sleep to wakefulness (WAKE), supporting their role in arousal. Conversely, DA decreased in the CeA and nucleus accumbens lateral parts (NAc-L) during these transitions. During transitions from NREM to rapid eye movement sleep (REM), DA elevations were observed in the CeA and middle accumbens subregion (NAc-M), rather than NAc-L, while other regions exhibited decreases. Cross-regional DA correlations revealed synchronized network activity across sleep-wake transitions. Optogenetic activation of VTA and DRN dopamine neurons induced robust DA release in cortical and subcortical regions, and chemogenetic activation promoted wakefulness selectively via VTA and DRN, but not SNc DA neurons. These results elucidate distinct brainwide DA dynamics across state transitions and highlight differential roles for DA signaling in modulating sleep-wake states.

neuroscience↗

bioRxiv2026

An Asynchronous Production Line of Meiotic Prophase I in the Mouse Fetal Ovary

The initiation of meiosis in the mammalian female germline has long been described as a synchronous event, occurring within a narrow developmental window. Here, we challenge this paradigm through a systematic, quantitative analysis of meiotic entry and progression in the mouse fetal ovary. Using dynamic expression profiling of key regulators Stra8, Sycp1, and Sycp3 alongside proliferation markers, we demonstrate that germ cells enter meiosis asynchronously and continuously between embryonic days E12.5 and E16.5. During this extended period, mitotic proliferation persists, indicating that germ cells are progressively recruited into the meiotic pathway rather than halting division simultaneously. Homologous chromosome synapsis, marked by Sycp1/Sycp3 co-localization, initiates at E14.5 and is completed prenatally by E18.5. Integrating these data into a continuous-time Markov chain model, we derive a "meiotic clock" that predicts fixed temporal intervals from meiotic entry to synapsis completion ([~]72 hours) and to meiotic arrest ([~]91 hours), regardless of entry time. This model provides a predictive framework for germ cell development and establishes that female meiotic initiation is a prolonged, asynchronous production line rather than a synchronized transition, reshaping our understanding of oogenesis and its regulatory logic. TEASERThe initiation of female meiosis in mice is redefined as an asynchronous, continuous production line from E12.5 to E16.5, supported by a predictive "meiotic clock" model with fixed temporal intervals for synapsis and arrest.

developmental biology↗

bioRxiv2025

SNAP: Streamlined Nextflow Analysis Pipeline for Immunoprecipitation-Based Epigenomic Profiling of Circulating Chromatin

Epigenomic profiling of circulating chromatin is a powerful and minimally invasive approach for detecting and monitoring disease, but there are no bioinformatics pipelines tailored to the unique characteristics of cell-free chromatin. We present SNAP (Streamlined Nextflow Analysis Pipeline), a reproducible, scalable, and modular workflow specifically designed for immunoprecipitation-based methods for profiling cell-free chromatin. SNAP incorporates quality control metrics optimized for circulating chromatin, including enrichment score and fragment count thresholds, as well as direct estimation of circulating tumor DNA (ctDNA) content from fragment length distributions. It also includes SNP fingerprinting to enable sample identity verification. When applied to cfChIP-seq and cfMeDIP-seq data across multiple cancer types, SNAPs quality filters significantly improved classification performance while maintaining high data retention. Independent validation using plasma from patients with osteosarcoma confirmed the detection of tumor-associated epigenomic signatures that correlated with ctDNA levels and reflected disease biology. SNAPs modular architecture enables straightforward extension to additional cell-free immunoprecipitation-based assays, providing a robust framework to support studies of circulating chromatin broadly. SNAP is compatible with cloud and high-performance computing environments and is publicly available at https://github.com/prc992/SNAP/. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/694452v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@47c734org.highwire.dtl.DTLVardef@674af8org.highwire.dtl.DTLVardef@16ae938org.highwire.dtl.DTLVardef@1f57a01_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Ultrasonic Reporter of Kinase Activity

Protein kinases are an essential class of enzymes that regulate cellular signaling pathways, with their dysregulation implicated in pathologies such as cancer and neurodegenerative diseases. Despite the existence of high-performance fluorescent biosensors of kinase activity, it remains challenging to study the function and regulation pathways of kinases in opaque tissues due to the limited tissue penetration of light. To address this limitation, we introduce the first ultrasonic reporter of kinase activity (UReKA), designed to detect protein kinase A (PKA) activity by altering the ultrasound scattering of gas vesicles, a unique class of air-filled protein nanostructures. We engineer a gas vesicle shell protein to respond to PKA, demonstrate the functionality of UReKA both in purified protein format and expressed in mammalian cells, and showcase its capacity to monitor PKA signaling in response to pharmacological stimulation or genetic mutation. This work makes it possible to visualize cellular functional activity in opaque media, with broad potential for future applications in cancer biology, cellular development, and drug discovery.

bioengineering↗

bioRxiv2025

A generalizable cross-continent prediction of esophageal squamous cell carcinoma using the oral microbiome

Esophageal squamous cell carcinoma (ESCC) is a disease with limited tools for early screening and a poor prognosis. Symptoms typically appear late, and early cancer is hard to detect without endoscopic screening, which is inaccessible in most high-risk areas. Saliva is easily accessible, and its microbiome composition can serve as a marker for upper gastrointestinal tract disease. We studied the potential utility of an oral microbiome signature for ESCC in South Africa, a region with a high incidence of the disease. In a cohort of 48 ESCC patients and 110 controls, we found marked alterations in the oral microbiome in patients with ESCC, including significantly reduced alpha diversity and increased Fusobacterium nucleatum. We devised machine learning models that classify ESCC using microbiome data, finding good performance on held-out samples (area under receiver operating characteristic curve of 0.96), and demonstrated generalization to data across independent studies conducted in different geographic regions (0.64-0.81). Overall, our results demonstrate the potential of the oral microbiome to serve as a non-invasive screening tool for ESCC.

microbiology↗

bioRxiv2025

Circulating chromatin reveals the effects of disease-associated variants on gene regulation

A fundamental challenge in human genetics is determining how variation in regulatory DNA shapes complex traits and disease risk. Chromatin quantitative trait loci (cQTLs) can address this challenge by revealing the effects of disease-linked genetic variants on regulatory element activity. Discovering cQTLs in disease-relevant tissues at scale remains challenging, however. To address this limitation, we leveraged advances in epigenomic liquid biopsy. We profiled histone modifications in circulating chromatin from patients with cancer to identify cell-free chromatin QTLs (cfcQTLs). By sampling cancer-derived chromatin in plasma, we captured cfcQTLs affecting regulatory elements from diverse non-hematologic tissues, as well as developmentally restricted elements that are reactivated in cancer (enriched 16-fold). Applying a cistrome-wide association study (CWAS), we linked 4,891 cfcQTLs to 1,011 traits and diseases. Developmentally restricted cfcQTLs that were not found in white blood cells were associated with 22.7 traits per 100 QTLs, compared to 0.58 for WBC-restricted cQTLs, underscoring the power of cfcQTLs for capturing genetic variation that shapes phenotypes. We extended our approach beyond germline variants to non-coding somatic mutations in cancer by measuring the activating effects of TERT promoter mutations from circulating chromatin. This work provides a path to scalable discovery of cQTLs across tissues, diseases, and populations to dissect the genetics of common diseases, enabled by the ease of sampling blood.

genomics↗

bioRxiv2025

Delivery of collagen-encoding mRNA to the skin for cosmetic applications

Collagens, the predominant structural proteins in mammalian, maintain tissue integrity through its unique triple-helical conformation. Traditionally, cosmetic collagens have been administered as hydrolyzed peptides derived from animal sources, which exhibit poor bioavailability and functional efficacy due to limited skin penetration and disrupted tertiary/quaternary structures. To overcome these limitations, we developed a novel system for in vivo collagen expression. This system utilizes the topical application of in vitro synthesized, AI-designed mRNAs encoding types I, III, and XVII collagens to improve human skin condition. Significant upregulation of target collagen expression was observed in dermal fibroblasts, leading to improved skin condition through in situ assembly of collagens in natural conformation.

bioengineering↗

bioRxiv2025

Predictive vision-language integration in the human visual cortex

Integrating linguistic and visual information is a core function of human cognition, yet how information from these two modalities interacts in the brain remains largely unknown. Competing frameworks, including the hub-and-spoke model and Bayesian theories such as predictive coding, offer conflicting accounts of how the brain achieves multimodal integration. To address this question, we collected a large-scale fMRI dataset and leveraged state-of-the-art AI systems to construct encoding models that probe how the human brain matches and integrates linguistic and visual information. We found that prior information from one modality can modulate neural responses in another, even in the early visual cortex (EVC). Integration neural response in EVC is governed by prediction errors consistent with predictive coding theory. Enhanced and suppressed neural responses to semantically matched cross-modal stimuli were found in distinct EVC populations, with suppression population carrying denser, behaviorally relevant semantic information. Both populations support semantic integration with distinct temporal dynamics and representational structures. These findings provide representational- and computational-level insights into how the brain integrates information across modalities, revealing unified principles of information processing that link biological and artificial intelligence.

neuroscience↗

bioRxiv2025

De Novo Design of Anti-Aging Peptides

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

bioinformatics↗

bioRxiv2025

Dual Targeting of IKKβ and NR4A1 for AML Therapy

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKK{beta}-NF-{kappa}B pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKK{beta} has been limited by serious toxicities, including neutrophilia. Here we identify IKK{beta} and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKK{beta} and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKK{beta} and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrols ability to bind both IKK{beta} and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKK{beta} and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKK{beta} and NR4A1 as a promising therapeutic strategy. Plain language summaryAcute myeloid leukemia (AML) is a predominant form of blood cancer with devastating consequences in both young and adult populations. Despite some advances in AML treatment over the last decade, there is still an unmet medical need to develop new drugs for difficult-to- treat AMLs. We discover that two proteins, namely IKK{beta} and NR4A1, play important roles in promoting the AML disease and could be associated with more severe AML subtypes. To target and destroy those proteins within AML cells, we employ a novel targeted protein degradation approach, which involved design, synthesis, and screening of PROTAC drugs, to discover a drug possessing pronounced AML cell killing activity by virtue of IKK{beta} and NR4A1 degradations. The drug also significantly reduces AML progression in mice without any noticeable adverse effects. Our current efforts involve more comprehensively testing the benefit of the drug (and its analogs) in a wide range of clinically relevant AML models. Key PointsO_LIIKK{beta} and NR4A1 are clinically relevant drivers of AML pathogenesis. C_LIO_LIA novel celastrol-based PROTAC can effectively degrade IKK{beta} and/or NR4A1 to potentially treat AML. C_LI

cancer biology↗

bioRxiv2025

Hepatocyte FAM210A deficiency disrupts mitochondrial function and triggers juvenile steatosis with compensatory repair in adulthood

Mitochondrial dynamics are central to maintaining liver metabolic homeostasis, yet the mechanisms that safeguarding mitochondrial integrity during development and metabolic dysfunction remain poorly defined. Here, we identify Family with sequence similarity 210 member A (FAM210A) as a hepatocyte-enriched mitochondrial regulator essential for postnatal liver maturation. Hepatocyte-specific deletion of Fam210a (Fam210aHKO) in mice caused early growth restriction, reduced body and liver mass, and pronounced hepatic steatosis with glycogen depletion. These defects were accompanied by lower postprandial glucose levels in the fasted-refeeding state, impaired oxidative phosphorylation, reduced mtDNA content, and abnormal cristae architecture. Transcriptomic and proteomic profiling revealed broad suppression of fatty acid, sterol, and bile acid metabolism, with concomitant glutathione stress responses. Mechanistically, FAM210A deficiency disrupted the YME1L-OPA1 axis, driving excessive OPA1 cleavage and cristae destabilization. Strikingly, these juvenile defects were transient and resolved by adulthood, underpinned by enhanced hepatocyte proliferation and mitochondrial biogenesis, consistent with a compensatory stress-adaptive response via the activation of ISR signaling. Together, these findings uncover FAM210A as a developmental safeguard of mitochondrial remodeling in hepatocytes and indicate compensatory programs with therapeutic relevance for chronic liver disease.

physiology↗

bioRxiv2025

Quantifying human adaptation to a novel split-belt walking condition after broad experience at different belt speeds

Humans can adapt their gait to minimize energy cost when given sufficient exposure to novel energy landscapes. However, it remains unclear whether broad experience in one energy landscape is sufficient to initiate continuous optimization when encountering similar but distinct conditions. In this study, we used visual biofeedback to guide 15 participants to broadly explore walking gaits with different step length asymmetries (SLAs) while walking on a split-belt treadmill with a large split-belt ratio. We subsequently tested how participants adapted their walking patterns during free exploration trials at the large split-belt ratio and at a new, smaller split-belt ratio. Our results showed that during guided exploration, participants were exposed to energetically favorable conditions. However, participants did not self-select walking patterns that minimized their metabolic cost during either free exploration trial. When first exposed to the smaller split-belt ratio, participants immediately adjusted their leg swing distances and belt contact times while maintaining similar step lengths. Throughout this trial, they continued adapting by significantly increasing step lengths on the fast belt. Taken together, our results suggest that participants actively modified their gait strategy when exposed to an energy landscape distinct from the one in which they gained broad experience.

neuroscience↗

bioRxiv2025

Angptl5 restricts primitive hematopoiesis by modulating retinoic acid signaling in zebrafish

Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult hematopoiesis. However, the mechanisms that modulate RA signaling in hematopoietic processes remain poorly understood. Using zebrafish as a model, we identified angiopoietin-like protein 5 (Angptl5) as a critical regulator of hematopoietic homeostasis. Loss of Angptl5 function resulted in myeloid hyperplasia in the anterior lateral plate mesoderm (ALPM) and anterior expansion of erythroid progenitors in the posterior lateral plate mesoderm (PLPM)-- phenotypes consistent with attenuated RA signaling. Molecular analyses confirmed impaired RA signaling in angptl5{Delta}10/{Delta}10 mutants, and exogenous RA supplementation fully rescued the hematopoietic defects. Mechanistically, we found that Angptl5 transcriptionally activates retinol dehydrogenase dhrs9 through its interaction with Integrin 6l{beta}5. Our findings establish Angptl5 as a novel and essential regulator of embryonic hematopoiesis and reveal a previously unrecognized mechanism controlling hematopoietic homeostasis. These insights position Angptl5 as a potential therapeutic target for hematological disorders.

developmental biology↗

bioRxiv2025

CNA detection from spatial transcriptomics using SpaCNA

Spatial transcriptomics (ST) enables genome-wide profiling of gene expression while preserving spatial context, yet accurate detection of copy number alterations (CNAs) in tumor ST data remain challenging. Here we present SpaCNA, a spatial-aware computational framework that integrates multi-modal spatial information to improve CNA detection. SpaCNA constructs adjacency graphs using spatial proximity and H&E stained image similarity, refines the raw gene expressions, and implements a Hidden Markov Random Field model for robust CNA state inference. Through extensive benchmarking on simulated data and multi-cancer cohorts, SpaCNA demonstrates superior accuracy and outperforms existing methods in CNA detection and tumor region identification. In real-world applications to breast cancer and colorectal cancer, SpaCNA reveals spatially distinct subclones with context-dependent interactions within the microenvironment. Additionally, applied to a 3D ST dataset of head and neck squamous cell carcinoma, SpaCNA uncovers clone-specific CNAs associated with therapeutic resistance biomarkers across multiple slices. By facilitating precise spatial mapping of CNAs and tumor architecture, SpaCNA significantly enhances our understanding of intratumoral heterogeneity and spatial evolutionary patterns.

bioinformatics↗

bioRxiv2025

Opposing effects of H2A.Z on memory, transcription and pathology in male and female Alzheimer's disease mice and patients

Alzheimers disease (AD) is a devastating neurodegenerative disease that disproportionately impacts women, but underlying mechanisms for sex-divergent outcomes are unknown. Here, we show that the histone variant H2A.Z is a novel sex-specific regulator of AD in human patients and AD model mice. Specifically, H2A.Z binding in chromatin declines in female and increases in male AD patients, indicating opposite patterns of AD-related H2A.Z dysregulation each sex. These sex differences were recapitulated in the 5xFAD model of AD, in which females accumulated H2A.Z at early disease stages and lost H2A.Z as the disease progressed, suggesting that H2A.Z occupancy shifts with advancing disease. Males showed no change in H2A.Z binding in early disease, but exhibited increased binding as disease progressed, albeit to a lesser extent than females. Consistent with sex-specific H2A.Z dysregulation, H2A.Z depletion produced sex-specific changes in gene expression, whereby H2A.Z was more repressive in female than in male mice and in 5xFAD than in WT males, suggesting that H2A.Zs role in transcription varies with sex and disease. Moreover, H2A.Z depletion improved memory and AD pathology in females, while impairing memory and worsening pathology in male mice. Together, these data suggest that H2A.Z is protective in males and detrimental in females with AD, with key implications for sex-specific therapeutic targeting of chromatin factors.

neuroscience↗

bioRxiv2024

BMP4 is sufficient to induce a caudal organizer

The caudal part of a vertebrate embryo consists of somites, neural tube, lateral plate mesoderm derivatives and the tailbud. However, the minimal conditions and factors sufficient to induce the caudal region, particularly in humans, remain unresolved. Here, we show that BMP4 alone, when administered at appropriate dosage, is sufficient to induce the formation of an organizer for caudal induction. This organizer induces caudal cell fate specification and morphogenesis in zebrafish embryos. In 3D human pluripotent stem cells (hPSCs) aggregates, BMP4 can induce an elongated embryonic structure characterized by caudal fates. Importantly, hPSCs instructed by BMP4 are sufficient to induce a secondary caudal region when grafted into the animal pole of the zebrafish embryo. Our study thus uncovers BMP4 as the inducer in the formation of a caudal organizer in the vertebrate embryo. Significance statementWe demonstrate that BMP4 alone can induce the formation of a caudal organizer, a critical structure that guides the development of the caudal region in vertebrates. Using zebrafish embryos, embryonic explants, human pluripotent stem cell xenografts, and 3D human stem cell aggregates, we show that this organizer replicates morphogenesis and key differentiation pathways seen in natural development. Our findings uncover a novel role for BMP4 and define the minimal requirements for inducing this organizer, offering new insights into vertebrate development and potential applications in regenerative medicine.

developmental biology↗