Biology subjects

Bu, X.

Publications and source records attributed to Bu, X..

16 recordsLinked to original sources

bioRxiv2026

Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles

Attention-deficit/hyperactivity disorder (ADHD) exhibits profound clinical heterogeneity; however, its underlying neurobiological substrates remain unclear. Here, leveraging large - scale structural magnetic resonance imaging data from 12,663 typically developing children and 1,699 children with ADHD across Chinese and United States cohorts, we construct population specific pediatric brain charts via hierarchical Bayesian normative modeling to quantify individual deviations in cortical morphology. Data-driven clustering identifies two robust, cross - ethnically replicable ADHD biotypes: an infra - normal biotype characterized by widespread cortical thinning and a supra - normal biotype marked by cortical thickening. Multivariate analyses reveal distinct brain-behavior architectures: cortical deviations correlate preferentially with symptom severity in the infra-normal biotype but with both symptom severity and cognitive performance in the supranormal biotype. Clinically, the infra-normal biotype demonstrates a superior response to methylphenidate over atomoxetine, whereas the supra-normal biotype responds comparably to both. Transcriptomic analyses identify biotype-specific molecular signatures converging with ADHD genome-wide association study (GWAS) risk loci but exhibiting distinct expression patterns in the brain. These findings classify ADHD heterogeneity into neurobiologically distinct, clinically informed biotypes, providing a mechanistic framework for precision psychiatry in pediatric ADHD.

neuroscience↗

bioRxiv2026

Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine's metabolite

A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamines antidepressant efficacy, yet their precise contributions remain poorly understood. Here, we demonstrate that one major metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets -{delta} opioid receptor heterodimers (-{delta}-ORs) on astrocytes. By promoting the formation and/or stabilization of -{delta}-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca{superscript 2} dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting -{delta}-OR assembly or Gs signaling abolishes HNK-mediated antidepressant responses both in vitro and in vivo. Collectively, astrocytic opioid receptor heterodimers are critical to antidepressant responses and HNK may serve as a prototype compound for targeting astrocyte dysfunction across a wide range of brain disorders.

neuroscience↗

bioRxiv2026

SigBridgeR: An Integrative Framework and Toolkit for Comprehensive Screening and Benchmarking of Phenotype-Associated Cell Subpopulations in Single-Cell Transcriptomics

Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, yet linking specific cell subpopulations to clinically relevant phenotypes remains a persistent challenge. Although multiple computational methods have been developed to bridge this gap, they are typically implemented as standalone packages with heterogeneous preprocessing pipelines, incompatible parameter conventions, and divergent output formats, thereby hindering rigorous cross-method benchmarking and reproducible multi-method workflows. Here, we present SigBridgeR, an extensible R framework and comprehensive toolkit that currently unifies eight state-of-the-art phenotype-associated cell screening algorithms within consistent workflows. We conducted a systematic benchmarking study across four cancer types HER2-positive breast cancer, triple-negative breast cancer, lung adenocarcinoma, and ovarian cancer using both binary phenotypes and patient survival endpoints. Our evaluation incorporated positive and negative control assessments based on differentially expressed genes and randomly selected marker panels, alongside quantitative accuracy comparisons using ground-truth cell labels. Building upon these insights, SigBridgeR provides standardized preprocessing for scRNA-seq and bulk transcriptomic data, unified algorithmic interfaces through a registry-based architecture, ensemble analysis via weighted voting, and comprehensive visualization utilities for multi-method comparison. By lowering technical barriers and promoting methodological standardization, SigBridgeR facilitates reliable discovery of phenotype-relevant cell subpopulations and enhances the translational potential of single-cell omics research.

bioinformatics↗

bioRxiv2026

Preserved Embedding of Neural Population Activity for Brain Computer Interfaces

Inferring neural population dynamics from motor cortex recordings is essential for brain-computer interface (BCI) control. However, neural activity patterns during similar behaviors exhibit systematic variability across recording sessions, subjects, and task contexts due to neural plasticity, anatomical differences, and varying movement distances. This variability degrades BCI decoder performanc when applied to different sessions, subjects, and task contexts. Here, we introduce Multi-Aligned Neural Data Transformer (MANDT) that extracts consistent embeddings of the motor cortical dynamics. By learning these consistent embeddings, MANDT enables generalization of BCI decoding: a decoder trained on data from one session maintains robust performance when applied to new sessions without recalibration. We validated our approach on neural recordings from rhesus monkeys performing the delayed-reach task. Lastly, we show that CEBRA can be used for the robotic control, enabling direct neural control of a humanoid robot, allowing monkeys to guide complex robotic manipulation tasks through brain signal.

neuroscience↗

bioRxiv2025

The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin

During meiosis, a group of evolutionarily conserved ZMM proteins plays essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, SHOC1 forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with meiotic arrest and male infertility, their precise molecular mechanisms and evolutionarily conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex, and identified a missense variant within the XPF-like domain in SHOC1 (c.A1769G:p.Q590R) that was associated with meiotic arrest and non-obstructive azoospermia (NOA). The disorder of the XPF-like domain in SHOC1 impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of M1AP, REDIC1, and ZMM factors to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic 3D chromatin structure in pachytene spermatocytes and induced defects in homologous chromosome synapsis. More importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby safeguarding critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study demonstrated that the XPF-like domain in SHOC1 is required for homologous recombination and safeguarding autosome from MSUC in meiosis.

developmental biology↗

bioRxiv2025

Testicular mRNA-LNP Delivery: A Novel Therapy for Genetic Spermatogenic Disorders

Uniform testicular maturation arrest is a severe form of male infertility characterized by the presence of germ cells that do not complete spermatogenic development. It is usually caused by meiotic arrest with genetic variants and difficult to treat via drugs or surgery. mRNA-lipid nanoparticle (LNP) delivery is a promising therapeutic option for maturation arrest with monogenic variants via protein replacement therapy. Herein, a spermatocytes-tropic LNP (Pool1-LNP3) was identified via a library of 30 ionizable lipids screening. And in vivo delivery of this novel LNP composition using rete testis microinjection was showed to be high spermatocytes targeting with high transfection efficiency. Thereafter, it was revealed that in vivo delivery of Pool1-LNP3 encapsulating Msh5 mRNA could promote crossover formation and restore spermatogenesis in Msh5D486Y/D486Y mouse models with DSB recombination defects. Notably, the offspring without genomic integration was born using intracytoplasmic sperm injection (ICSI) derived from rescue of Msh5D486Y/D486Ymouse and embryo transfer. Furthermore, no obvious inflammation and histologic damage in any tissue were detected after in vivo delivery of mRNA-LNP. In addition, it was demonstrated that Maps mRNA-LNP3 recovered spermatogenesis in Maps KO mouse with meiotic arrest. Altogether, these findings suggested that this spermatocytes-tropic mRNA-LNP delivery could become a viable and broad applicable strategy for treatment of spermatogenic disorders with genetic defects, providing a foundation for future clinical application.

molecular biology↗

bioRxiv2024

Cell crowding induces TRPV4 inhibition and its relocation to plasma membranes, implicating pro-invasive cell volume reduction mechanotransduction pathway

Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane- associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.

cell biology↗

bioRxiv2024

The Class III peroxidase OsPrx20 is a key regulator of stress response and growth in rice

In plants, reactive oxygen species maintain strictly low intracellular levels that is prerequisite for their function as second messengers. However, abiotic and biotic stresses are also long-term processes, requiring rapid scavenging of excess intracellular ROS. Plant Class III peroxidases, as multifunctional enzymes, are core enzymes in regulating intracellular ROS homeostasis and are key to regulating the complicated signaling network. Here, we found a rice Class III peroxidase OsPrx20 maintains intracellular ROS homeostasis in different conditions. OsPrx20 is a target of Ca2+/calmodulin-dependent protein kinase (OsDMI3) and phosphorylates its Thr-244 site by OsDMI3. Overexpression of OsPrx20 enhances osmotic stress tolerance but reduces blast resistance, while lack of OsPrx20 is opposite, suggesting OsPrx20 positively regulates osmotic stress tolerance but negatively regulates blast resistance in rice. Meanwhile, overexpression of OsPrx20 enlarges spike size and grain fullness, whereas lack of OsPrx20 leads to dwarfism and smaller spike. In ABA signaling, OsPrx20 Thr-244 phosphorylation is specifically dependent on OsDMI3 to reduce the sensitivity of ABA to seed germination and root growth and to enhance osmotic stress tolerance without affecting spike and grain development. Our study reveals an essential regulatory mechanism that directly activates OsPrx20 in ABA signaling, highlighting the multi-functionality of OsPrx20 in different biological processes.

plant biology↗

bioRxiv2024

Normative growth modeling of brain morphology reveals neuroanatomical heterogeneity and biological subtypes in children with ADHD

BackgroundNeuroimaging studies suggest substantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD). However, how these individual-level brain phenotypes contribute to the identification of ADHD biotypes and whether these biotypes have different treatment outcomes and neurobiological underpinnings remain largely unknown. MethodsWe collected multisite, high-quality structural magnetic resonance imaging data from 1,006 children aged 6-14 years, including 351 children with ADHD and 655 typically developing children. Normative growth models of cortical thickness were established for 219 regions in the typically developing children. Individual-level deviations from these normal references were quantified and clustered to identify ADHD biotypes. We validated the replicability and generalizability of the ADHD biotypes using two independent datasets and evaluated the associations of the biotypes with symptomatic, cognitive, and gene expression profiles, as well as follow-up treatment outcomes. FindingsNo more than 10% of children with ADHD had extreme deviations in cortical thickness in a single region, suggesting high heterogeneity among individuals with ADHD. On the basis of the brain deviation maps, we discovered two robust ADHD biotypes, an infra-normal subtype with cortical thinning associated with ADHD symptoms and a supranormal subtype with cortical thickening associated with cognition. Patients with the infra-normal subtype responded better to methylphenidate than to atomoxetine, although both subtypes showed treatment efficacy. Brain deviations in the infra-normal subtype were explained by the expression levels of genes enriched in presynaptic and axonal development and polygenic risk of ADHD. InterpretationWe identified anatomically distinct, clinically valuable, and biologically informed ADHD subtypes, providing insight into the neurobiological basis of clinical heterogeneity and facilitating a personalized medication strategy for ADHD patients. Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSubstantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD) motivates the need to discover homogeneous biotypes. We searched PubMed for research articles on ADHD biotypes using brain MRI published before December 1, 2023, using the search terms ((attention deficit hyperactivity disorder [Title/Abstract]) OR (ADHD [Title/Abstract])) AND ((subtypes [Title/Abstract]) OR (subgroups [Title/Abstract]) OR (subtyping [Title/Abstract])) AND ((MRI [Title/Abstract]) OR (neuroimaging [Title/Abstract]) OR (brain [Title/Abstract])) without language restrictions. Of the eight included studies, two identified ADHD biotypes using structural morphology, four used functional activity, and two used multimodal features. However, none of these studies considered the developmental effect of the brain phenotypes, examined treatment response, or investigated the genetic correlates of the biotypes. Added value of this studyThis study is the first to use individualized brain measures extracted from normative models to investigate ADHD biotypes in a large sample of more than 1,000 children. We identified two reproducible ADHD biotypes, characterized by distinct symptomatic, cognitive, and gene expression profiles, as well as differential treatment responses. This study advances our understanding of the neurobiological basis underlying the clinical heterogeneity of ADHD and highlights the critical need to discover ADHD biotypes using an unbiased and individualized approach. Implications of all the available evidenceThis study revealed remarkable neuroanatomical heterogeneity in ADHD patients and identified anatomically distinct, clinically valuable, and biologically informed ADHD biotypes. Our findings have potential value for the investigation of data-driven biotypes to evaluate treatment efficacy and facilitate personalized treatment. We also highlight the need for future studies to move beyond the understanding of ADHD solely based on the "average patient" perspective.

neuroscience↗

bioRxiv2024

CoRAL accurately resolves extrachromosomal DNA genomestructures with long-read sequencing

Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring in approximately 15% of early stage cancers and 30% of late-stage cancers. EcDNAs drive tumor formation, evolution, and drug resistance by dynamically modulating oncogene copy-number and rewiring gene-regulatory networks. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Paired-end short-read (Illumina) sequencing and mapping have been utilized to represent ecDNA amplifications using a breakpoint graph, where the inferred architecture of ecDNA is encoded as a cycle in the graph. Traversals of breakpoint graph have been used to successfully predict ecDNA presence in cancer samples. However, short-read technologies are intrinsically limited in the identification of breakpoints, phasing together of complex rearrangements and internal duplications, and deconvolution of cell-to-cell heterogeneity of ecDNA structures. Long-read technologies, such as from Oxford Nanopore Technologies, have the potential to improve inference as the longer reads are better at mapping structural variants and are more likely to span rearranged or duplicated regions. Here, we propose CoRAL (Complete Reconstruction of Amplifications with Long reads), for reconstructing ecDNA architectures using long-read data. CoRAL reconstructs likely cyclic architectures using quadratic programming that simultaneously optimizes parsimony of reconstruction, explained copy number, and consistency of long-read mapping. CoRAL substantially improves reconstructions in extensive simulations and 9 datasets from previously-characterized cell-lines as compared to previous short-read-based tools. As long-read usage becomes wide-spread, we anticipate that CoRAL will be a valuable tool for profiling the landscape and evolution of focal amplifications in tumors.

cancer biology↗

bioRxiv2024

Spike Neural Network of Motor Cortex Model for Arm Reaching Controlling

Motor cortex modeling is crucial for understanding movement planning and execution. While interconnected recurrent neural networks have successfully described the dynamics of neural population activity, most existing methods utilize continuous signal-based neural networks, which do not reflect the biological spike neural signal. To address this limitation, we propose a recurrent spike neural network to simulate motor cortical activity during an arm-reaching task. Specifically, our model is built upon integrate-and-fire spiking neurons with conductance-based synapses. We carefully designed the interconnections of neurons with two different firing time scales - "fast" and "slow" neurons. Experimental results demonstrate the effectiveness of our method, with the models neuronal activity in good agreement with monkeys motor cortex data at both single-cell and population levels. Quantitative analysis reveals a correlation coefficient 0.89 between the models and real data. These results suggest the possibility of multiple timescales in motor cortical control.

neuroscience↗

bioRxiv2023

Internal Dynamics Interact with Proprioceptive Feedback During Movement Execution in an RNN Model of Motor Cortex

Proprioceptive feedback provides the information about the state of the body, which is critical in motor control. However, the contribution of proprioceptive feedback to motor cortical activity during voluntary movement execution is unclear. Here, we built an recurrent neural network model of motor cortex that receives proprioceptive feedback, and optimized it to control a virtual arm to perform a delayed-reach task. Simulated neural activity is similar to real data, indicating that our model captures the motor cortical dynamics. We further disrupted recurrent connectivity and proprioceptive feedback to dissect their contribution, and found that internal dynamics dominate in neural population activity, while proprioceptive feedback controls movement termination. Moreover, proprioceptive feedback improves the networks robustness against noisy initial conditions. We further investigated the relative importance of the components in proprioceptive feedback and found that the feedback of hand velocity contributes most to the similarity between simulation and real data. Finally, we show that our motor cortex model can be implemented in the sensorimotor system, demonstrating our models biological plausibility. In summary, motor command may arise from the intersection between recurrent dynamics in motor cortex and proprioceptive feedback.

neuroscience↗

bioRxiv2023

A PARP inhibitor, rucaparib, improves cardiac dysfunction in ADP-ribose-acceptor hydrolase 3 (Arh3) deficiency

AimsPatients with ADP-ribose-acceptor hydrolase 3 (ARH3) deficiency exhibit stress-induced childhood-onset neurodegeneration with ataxia and seizures (CONDSIAS). ARH3 degrades protein-linked poly(ADP- ribose) (PAR) synthesized by poly(ADP-ribose)polymerase (PARP)-1 during oxidative stress, leading to cleavage of the ADP-ribose linked to protein. ARH3 deficiency leads to excess accumulation of PAR, resulting in PAR-dependent cell death or parthanatos. Approximately one-third of patients with homozygous mutant ARH3 die from cardiac arrest, which has been described as neurogenic, suggesting that ARH3 may play an important role in maintaining myocardial function. To address this question, cardiac function was monitored in Arh3-knockout (KO) and - heterozygous (HT) mice. Methods and resultsArh3-KO male mice displayed cardiac hypertrophy by histopathology and decreased cardiac contractility assessed by MRI. In addition, both genders of Arh3-KO and -HT mice showed decreased cardiac contractility by dobutamine stress test assessed by echocardiography. A direct role of ARH3 on myocardial function was seen with a Langendorff-perfused isolated heart model. Arh3-KO male mouse hearts showed decreased post-ischemic rate pressure products, increased size of ischemia-reperfusion (IR) infarcts, and elevated PAR levels. Consistently, in vivo IR injury showed enhanced infarct size in Arh3-KO mice in both genders. In addition, Arh3-HT male mice showed increased size of in vivo IR infarcts. Treatment with an FDA-approved PARP inhibitor, rucaparib, improved cardiac contractility during dobutamine-induced stress and exhibited reduced size of in vivo IR infarcts. To understand better the role of ARH3, CRISPR-Cas9 was used to generate different Arh3 genotypes of myoblasts and myotubes. Incubation with H2O2 decreased viability of Arh3-KO and -HT myoblasts and myotubes, resulting in PAR-dependent cell death that was reduced by PARP inhibitors or by transfection with the Arh3 gene. ConclusionARH3 regulates PAR homeostasis in myocardium to preserve function and protect against oxidative stress; PARP inhibitors reduce the myocardial dysfunction seen with Arh3 mutations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/527369v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@a76514org.highwire.dtl.DTLVardef@1dd3184org.highwire.dtl.DTLVardef@ddfd26org.highwire.dtl.DTLVardef@16e0cd_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Connectome-wide association analysis identified significant brain functional alteration in adults with attention-deficit/hyperactivity disorder

Adults with attention-deficit/hyperactivity disorder (ADHD), as an extreme-phenotype of ADHD, is still facing problems of inconsistency and undeciphered mechanisms for its neuropathology. To address this matter, our present study performed connecotome-wide voxel-based analyses with the resting-state fMRI data of 84 adults with ADHD and 89 healthy controls. We found that functional connectivity patterns of the left precuneus and the left middle temporal significantly altered in ADHD populations serving as potential neural biomarkers to distinguish ADHD with healthy controls, with subsequent seed-based analysis revealing the dysfunction of functional connections both intra- and inter-default mode and attention networks, among which middle temporal gyrus plays the key role of bridge linking the default mode and attention networks. After cognitive behavioral therapy, two of these ADHD-altered functional connections ameliorated accompanied with improvement of ADHD core symptoms. Additionally, imaging genetic analyses also revealed close relationships between the observed brain functional alterations and ADHD-risk genes. Taken together, our findings suggested the interference of default mode on attention networks in adults with ADHD, which would be severing as a potential biomarker for both ADHD pathogenesis and treatment effects.

neuroscience↗

bioRxiv2018

Migration of gastric cancer is suppressed by rabies virus glycoprotein via regulating α7-nicotinic acetylcholine receptors/ERK-EMT

Nicotinic acetylcholine receptors (nAChRs) have been reported to be overexpressed in malignancies in humans and is associated with tumorigenesis and cell migration. In previous studies of gastric cancer, alpha7 nicotinic acetylcholine receptor (7-nAChR) overexpression can induce epithelial-mesenchymal transition (EMT) and promote migration of gastric cancer cells. Recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) may promote apoptosis of gastric cancer cells and reduces migration of lung cancer metastasis. However, whether rL-RVG inhibits migration of gastric cancer cells and what the underlying functional mechanism is remains unknown. In this study, our findings demonstrate that rL-RVG suppressed migration and reduced EMT of gastric cancer cells via 7-nAChR in vitro. Furthermore rL-RVG decreased the phosphorylation levels of the MEK/ERK signaling pathway such as down-regulating the expression of P-MEK and P-ERK. Additionally, rL-RVG also reduced the expression level of mesenchymal markers N-cadherin and Vimentin and enhanced the expression of the epithelial marker E-cadherin. Lastly, rL-RVG together with nicotinic acetylcholine receptors (nAChRs) inhibited gastric cancer epithelial to mesenchymal transition (EMT) which suppressed gastric cancer cell migration. We also found that rL-RVG suppresses the growth of gastric cancer subcutaneous tumor cells in vivo. Thus, rL-RVG inhibits 7-nAChR-MEK/ERK-EMT to suppress migration of gastric cancer cells.

cancer biology↗

bioRxiv2018

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Paracellular barriers play an important role in the pathogenesis of IBDs and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumor suppressor gene and inhibits colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Here, We found that intestine-specific Ndrg2 deficiency caused mild spontaneous colitis with ageing, aggravated DSS and TNBS induced colitis, increased AOM-DSS induced colitis-associated tumor. Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhancing the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination, and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays important role in gut homeostasis maintenance and colitis-associated tumor development. SUMMARYAdherens junctoin (AJ) as the key part of intestinal epithelial barrier plays important role in the pathogenesis of IBDs. Intestinal specific Ndrg2 loss attenuates E-cadherin expression and disrupts the integrity of AJ structure which is feasible for colitis and tumor development.

cancer biology↗