Biology subjects

Fan, X.

Publications and source records attributed to Fan, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk

MicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.

bioinformatics↗

bioRxiv2024

Unravelling the progression of the zebrafish primary body axis with reconstructed spatiotemporal transcriptomics

Elucidating the spatiotemporal dynamics of gene expression is essential for understanding complex physiological and pathological processes. Traditional technologies like in situ hybridization (ISH) and immunostaining have been restricted to analyzing expression patterns of a limited number of genes. Spatial transcriptomics (ST) has emerged as a robust alternative, enabling the investigation of spatial patterns of thousands of genes simultaneously. However, current ST methods are hindered by low read depths and limited gene detection capabilities. Here, we introduce Palette, a pipeline that infers detailed spatial gene expression patterns from bulk RNA-seq data, utilizing existing ST data as only reference. This method identifies more precise expression patterns by smoothing, imputing and adjusting gene expressions. We applied Palette to construct the Danio rerio SpatioTemporal Expression Profiles (DreSTEP) by integrating 53-slice serial bulk RNA-seq data from three developmental stages with existing ST references and 3D zebrafish embryo images. DreSTEP provides a comprehensive cartographic resource for examining gene expression and spatial cell-cell interactions within zebrafish embryos. Utilizing machine learning-based screening, we identified key morphogens and transcription factors (TFs) essential for anteroposterior (AP) axis development and characterized their dynamic distribution throughout embryogenesis. In addition, among these TFs, Hox family genes were found to be pivotal in AP axis refinement. Their expression was closely correlated with cellular AP identities, and hoxb genes may act as central regulators in this process.

developmental biology↗

bioRxiv2024

Digital pathology assessment of kidney glomerular filtration barrier ultrastructure in an animal model of podocytopathy

BackgroundTransmission electron microscopy (TEM) images can visualize kidney glomerular filtration barrier ultrastructure, including the glomerular basement membrane (GBM) and podocyte foot processes (PFP). Podocytopathy is associated with glomerular filtration barrier morphological changes observed experimentally and clinically by measuring GBM or PFP width. However, these measurements are currently performed manually. This limits research on podocytopathy disease mechanisms and therapeutics due to labor intensiveness and inter-operator variability. MethodsWe developed a deep learning-based digital pathology computational method to measure GBM and PFP width in TEM images from the kidneys of Integrin-Linked Kinase (ILK) podocyte-specific conditional knockout (cKO) mouse, an animal model of podocytopathy, compared to wild-type (WT) control mouse. We obtained TEM images from WT and ILK cKO littermate mice at 4 weeks old. Our automated method was composed of two stages: a U-Net model for GBM segmentation, followed by an image processing algorithm for GBM and PFP width measurement. We evaluated its performance with a 4-fold cross-validation study on WT and ILK cKO mouse kidney pairs. ResultsMean (95% confidence interval) GBM segmentation accuracy, calculated as Jaccard index, was 0.73 (0.70-0.76) for WT and 0.85 (0.83-0.87) for ILK cKO TEM images. Automated and manual GBM width measurements were similar for both WT (p=0.49) and ILK cKO (p=0.06) specimens. While automated and manual PFP width measurements were similar for WT (p=0.89), they differed for ILK cKO (p<0.05) specimens. WT and ILK cKO specimens were morphologically distinguishable by manual GBM (p<0.05) and PFP (p<0.05) width measurements. This phenotypic difference was reflected in the automated GBM (p<0.05) more than PFP (p=0.06) widths. ConclusionsThese results suggest that certain automated measurements enabled via deep learning-based digital pathology tools could distinguish healthy kidneys from those with podocytopathy. Our proposed method provides high-throughput, objective morphological analysis and could facilitate podocytopathy research and translate into clinical diagnosis. Key pointsO_LIWe leveraged U-Net architecture in an algorithm to measure the widths of glomerular basement membrane and podocyte foot processes. C_LIO_LIDeep learning-based automated measurement of glomerular filtration barrier morphology has promise in podocytopathy research and diagnosis. C_LI

pathology↗

bioRxiv2024

Preventing trogocytosis by cathepsin B inhibition augments CAR T cell function

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which has been suggested to cause CAR T cell fratricide and exhaustion. Whether CMT indeed causes CAR T cell dysfunction and the molecular mechanisms conferring CMT remain unknown. Using a selective degrader of trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen on the CAR T cell surface directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we found that the cysteine protease cathepsin B is essential for CMT and that inhibition of cathepsin B is sufficient to prevent CAR T cell fratricide and exhaustion, leading to improved long-term CAR T cell persistence and anti-tumor activity. Our data demonstrate that it is feasible to separate CMT from cytotoxic activity, that CAR T cell persistence, a key factor associated with clinical CAR T cell efficacy, is directly linked to cathepsin B activity in CAR T cells, and that it is possible to improve CAR T cell function through selective inhibition of CMT. One sentence summary: CAR-mediated trogocytosis is mediated by the cysteine protease cathepsin B and directly causes CAR T cell exhaustion and fratricide. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/598379v3_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@5c058dorg.highwire.dtl.DTLVardef@1707fa7org.highwire.dtl.DTLVardef@ccdff1org.highwire.dtl.DTLVardef@82800b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Insula uses overlapping codes for emotion in self and others

In daily life, we must recognize others emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

neuroscience↗

bioRxiv2024

Pioneer factor ETV2 safeguards endothelial cell specification by recruiting the repressor REST to restrict alternative lineage commitment

Mechanisms of cell fate specification remain a central question for developmental biology and regenerative medicine. The pioneer factor ETV2 is a master regulator for the endothelial cell (EC) lineage specification. Here, we studied mechanisms of ETV2-driven fate specification using a highly efficient system in which ETV2 directs human induced pluripotent stem cell-derived mesodermal progenitors to form ECs over two days. By applying CUT&RUN, single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses, we characterized the transcriptomic profiles, chromatin landscapes, dynamic cis-regulatory elements (CREs), and molecular features of EC cell differentiation mediated by ETV2. This defined the scope of ETV2 pioneering activity and identified its direct downstream target genes. Induced ETV2 expression both directed specification of endothelial progenitors and suppressed acquisition of alternative fates. Functional screening and candidate validation revealed cofactors essential for efficient EC specification, including the transcriptional activator GABPA. Surprisingly, the transcriptional repressor REST was also necessary for efficient EC specification. ETV2 recruited REST to occupy and repress non-EC lineage genes. Collectively, our study provides an unparalleled molecular analysis of EC specification at single-cell resolution and identifies the important role of pioneer factors to recruit repressors that suppress commitment to alternative lineages.

cell biology↗

bioRxiv2024

Contribute to balance, wire in accordance: Emergence of backpropagation from a simple, bio-plausible neuroplasticity rule

Over the past several decades, backpropagation (BP) has played a critical role in the advancement of machine learning and remains a core method in numerous computational applications. It is also utilized extensively in comparative studies of biological and artificial neural network representations. Despite its widespread use, the implementation of BP in the brain remains elusive, and its biological plausibility is often questioned due to inherent issues such as the need for symmetry of weights between forward and backward connections, and the requirement of distinct forward and backward phases of computation. Here, we introduce a novel neuroplasticity rule that offers a potential mechanism for implementing BP in the brain. Similar in general form to the classical Hebbian rule, this rule is based on the core principles of maintaining the balance of excitatory and inhibitory inputs as well as on retrograde signaling, and operates over three progressively slower timescales: neural firing, retrograde signaling, and neural plasticity. We hypothesize that each neuron possesses an internal state, termed credit, in addition to its firing rate. After achieving equilibrium in firing rates, neurons receive credits based on their contribution to the E-I balance of postsynaptic neurons through retrograde signaling. As the networks credit distribution stabilizes, connections from those presynaptic neurons are strengthened that significantly contribute to the balance of postsynaptic neurons. We demonstrate mathematically that our learning rule precisely replicates BP in layered neural networks without any approximations. Simulations on artificial neural networks reveal that this rule induces varying community structures in networks, depending on the learning rate. This simple theoretical framework presents a biologically plausible implementation of BP, with testable assumptions and predictions that may be evaluated through biological experiments.

neuroscience↗

bioRxiv2024

Spatiotemporal transcriptomic maps of mouse intracerebral hemorrhage at single-cell resolution

Intracerebral hemorrhage (ICH) is a severe and widespread disease that results in high mortality and morbidity. Despite significant advances made in clinical and preclinical research, the prognosis of ICH remains poor due to an incomplete understanding of the complex pathological responses. To address this challenge, we generated single-cell resolution spatiotemporal transcriptomic maps of mouse brain 1, 3, 7, 14, and 28 days after ICH. Our analysis revealed the cellular constituents and their dynamic responses following ICH. We found changes in gene expression that are indicative of active phagocytosis and lipid processing in the lesion core and identified genes associated with brain repair at the lesion border. Persistent lipid accumulation culminated in the phenotypic transition of macrophages into foam cells. Furthermore, our results demonstrate that ICH could stimulate neural stem cells in the subventricular zone, thereby enhancing neurogenesis in this niche. This study provides a spatiotemporal molecular atlas of mouse ICH that advances the understanding of both local and global responses of brain cells to ICH and offers a valuable resource that can aid the development of novel therapies for this devastating condition.

neuroscience↗

bioRxiv2024

Characterizing interactions of ER resident proteins in situ through the YST-PPI method

The mutual interactions of ER resident proteins in the ER maintain its functions, prompting the protein folding, modification, and transportation. Here, a new method, named YST-PPI (YESS-based Split fast TEV protease System for Protein-protein Interaction) was developed, targeting the characterization of protein interactions in ER. YST-PPI method integrated the YESS system, split-TEV technology and endoplasmic reticulum retention signal peptide (ERS) to provide an effective strategy for studying ER in situ PPIs in a fast and quantitative manner. The interactions among 15 ER resident proteins of S. cerevisiae were explored using the YST-PPI system, and their interaction network map was constructed, in which more than 74 interacting resident protein pairs were identified. Our studies also showed that Lhs1p plays a critical role in regulating the interactions of most of the ER resident proteins, expect the Sil1p, indicating its potential role in controlling the ER molecular chaperones. Moreover, the mutual interaction revealed by our studies further confirmed that the ER resident proteins perform their functions in a synergetic way and multimer complex might be formed during the process.

microbiology↗

bioRxiv2024

Sacrificing Adaptability for Functionality: The Ivory Tower of Macular Muller Cells

The predilection of many retinal diseases for the macula suggests it may be less resistant to stress than the peripheral retina. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited more transcriptional changes than the macula in response to stress. One pronounced change was in a subgroup of Muller cells (MCs) that were dominant in the peripheral retina. Genes more abundantly expressed in peripheral MCs were mainly associated with stress responses and were more influenced by light stress. In contrast, genes highly expressed in MCs that predominated in the macula had roles in cellular function and were less influenced by light stress. Metallothionein 1, A Kinase Anchor Protein 12 and MAF BZIP Transcription Factor F were more abundantly expressed in peripheral MCs than in macular MCs. Knockdown of these genes in primary MCs reduced their viability under stress. Our findings indicate that macular MCs are more directed toward maintaining retinal function rather than mounting a stress response when exposed to stress, which may contribute to the maculas vulnerability to degenerative diseases.

neuroscience↗

bioRxiv2024

The enhancement of electricity generation using cellulose based on ternary microbial consortium

Cooperation between microorganisms is crucial to design an efficient inoculum for enhancing the electricity-producing ability of carboxymethyl cellulose (CMC) fed bioreactors. In the present study, the influence of microbial mutualistic interactions and electricity generation capability were investigated by designing several co-culture and ternary culture systems. It was found that a ternary culture system of Cellulomonas Lsc-8, Bacillus subtilis C9 and Geobacter sulfurreducens PCA was used to efficiently convert cellulose into electricity. The maximum current density of 796 {+/-} 30 {micro}A{middle dot}cm-2 were achieved by the ternary culture, which were much higher than that Geobacter sulfurreducens PCA using acetate and co-culture systems to utilize CMC in bioreactors, respectively. In this consortium, Cellulomonas Lsc-8, and Bacillus subtilis C9 simultaneously digested CMC to produce acetate and secreted riboflavin as an electron shuttle; Geobacter sulfurreducens PCA utilized acetate to generate electricity. The introduction of Bacillus subtilis C9 further promoted the degradation of CMC and secreted more riboflavin to enhance electricity generation of the ternary culture. This work suggested that the synergistic interaction between interspecies in microbial consortia is emergent in designing specific community for achieving maximum power generation using CMC as substrate. This research shows new insight into the design of more efficient, stable, and robust microbial consortia applicable in waste treatment and power generation. IMPORTANCEMicrobial fuel cells (MFCs) may benefit from microbial consortia that efficiently convert carbon sources to electricity. A key challenge with this system is how to manage microbial community assembly to maximize electricity generation. Herein, we constructed and tested a three-species microbial consortium to enhance conversion of cellulose to electricity. Cellulomonas Lsc-8 and Bacillus subtilis C9 efficiently converted cellulose to acetate (electron donor) and riboflavin (electron shuttle), which enabled Geobacter sulfurreducens to generate electricity. This study laid the foundation for design of more efficient, stable, and robust microbial consortia for waste treatment and energy applications.

microbiology↗

bioRxiv2024

Regulatory Functional Landscape of the HMX1 Gene for Normal Ear Development

Enhancers, through the combinatorial action of transcription factors (TFs), dictate both the spatial specificity and the levels of gene expression, and their aberrations can result in diseases. The association between HMX1 and its downstream enhancer with ear deformities has been previously documented. However, the pathogenic variations and molecular mechanisms underlying the bilateral constricted ear (BCE) malformations remain unclear. This study identifies a copy number variation (CNV) encompassing three enhancers that induces BCE. These enhancers, collectively termed the positional identity hierarchical enhancer cluster (PI-HEC), co-regulate spatiotemporal expression of the HMX1 gene in a coordinated and synergistic mode, each displaying unique activity-location-structure characteristics. A thorough exploration of this regulatory locus reveals that specific motif clusters within the PI-HEC variably modulate its activity and specificity, with the high mobility group (HMG) box combined with Coordinator and homeodomain (HD)-TFs notably influencing them respectively. Our findings based on various types of mouse models, reveal that both aberrant Hmx1 expression in the fibroblasts of the basal pinna, originating from neural crest cells, and ectopic expression in the distal pinna structures contribute to the abnormal development of the outer ear, including the cartilage, muscle, and epidermis tissues. This study deepens our understanding of mammalian ear morphogenesis and sheds light on the complexity of gene expression regulation by enhancers and specific sequence motifs.

developmental biology↗

bioRxiv2024

Non-invasive and painless mid-infrared modulation increases collagen in human and mouse skin

Stimulating collagen production in skin helps to enhance vitality while decelerating aging- associated processes in skin tissue. However, current approaches to enhancing collagen production are commonly limited by accompanying pain and trauma. Here, we report that mid-infrared modulation (MIMO) at an intensity of 70 mW/cm2 promotes collagen production in human or mouse skin in vivo without generating excessive heat. We found that protein levels of the collagen- degrading endopeptidase, MMP-1, were decreased in the skin of mice following MIMO treatment, whereas the collagen synthesis-related factors, TGF-{beta}, HSP47, and HSP70, were all increased. In addition, MIMO stimulated collagen secretion in human dermal fibroblasts in vitro. This work demonstrates that MIMO is an effective, non-invasive, and painless intervention for in vivo enhancement of collagen production in the skin. One Sentence SummaryMid-infrared modulation promotes collagen production

molecular biology↗

bioRxiv2024

Whole-genome resequencing revealed the Origin and Domestication of Chinese Domestic Rabbits

The evolutionary and genetic origins of Chinese indigenous rabbits (Oryctolagus cuniculus) remain largely unclear, despite being among the most recently domesticated animals. We sequenced the whole genomes of 142 individual rabbits and collected 25 resequencing accessions from the NCBI, representing six Chinese indigenous breeds, three other domesticated breeds (serving as a bridge between European wild-type and Chinese domestic populations), and two wild rabbit populations from the Iberian Peninsula and Southern France. Population and demographic analyses suggest that Chinese domestic rabbits are most likely descendants of O. c. cuniculus, native to France 800-1500 years ago. These rabbits likely first arrived in the southeast coastal areas of China through trade before spreading to inland regions. Additionally, there may be other origins for Chinese domestic rabbits. We observed considerable variation in the genetic makeup of maternal ancestry between Chinese domestic rabbits and European wild populations, with Chinese rabbits possessing unique mitochondrial haplotypes. Our analysis also highlights selective sweeps on genes affecting brain and neuronal development, which may have been under strong positive selection during domestication; genes related to starch digestion and fat metabolism, suggesting an evolutionary adaptation to digest high-starch diets; and the white coat phenotype in rabbits, resulting from selection at the melanogenesis-associated transcription factor locus. Overall, our data provide comprehensive insights into the origin and domestication of rabbits and lay the foundation for genome-based breeding.

evolutionary biology↗

bioRxiv2024

Deep learning based genomic breeding of pest-resistant grapevine

Crop pests have profoundly deleterious effects on crop yield and food security. However, conventional pest control depends heavily on the utilization of insecticides, which develops strong pesticide resistance and concerns of food safety. Crop and their wild relatives display diverse levels of pest resistance, indicating the feasibility for breeding of pest-resistant crop varieties. In this study, we integrate deep learning (DL)/machine learning (ML) algorithms, plant phenomics and whole genome sequencing (WGS) data to conduct genomic selection (GS) of pest-resistance in grapevine. We employ deep convolutional neural networks (DCNN) to accurately calculate the severity of damage by pests on grape leaves, which achieves a classification accuracy of 95.3% (Visual Geometry Group 16, VGG16, for binary trait) and a correlation coefficient of 0.94 in regression analysis (DCNN with Pest Damage Score, DCNN-PDS, for continuous trait). We apply DL models to predict and integrate phenotype (both binary and continuous) along with WGS data from 231 grape accessions, conducting Genome-Wide Association Studies (GWAS). This analysis detects a total of 69 QTLs, encompassing 139 candidate genes involved in pathways associated with pest resistance, including jasmonic acid (JA), salicylic acid (SA), ethylene, and other related pathways. Furthermore, through the combination with transcriptome data, we identify specific pest-resistant genes, such as ACA12 and CRK3, which play distinct roles in resisting herbivore attacks. Machine learning-based GS demonstrates a high accuracy (95.7%) and a strong correlation (0.90) in predicting the leaf area damaged by pests as binary and continuous traits in grapevine, respectively. In general, our study highlights the power of DL/ML in plant phenomics and GS, facilitating genomic breeding of pest-resistant grapevine.

plant biology↗

bioRxiv2024

Multivalent 28S rRNA Is the Organizer of the Nucleolus's Multi-layered Architecture

The nucleolus widely exists in all eukaryotic species. Throughout evolution, two types of nucleoli have emerged: bipartite, which has two-layered subcompartments, and tripartite, which features three nested sub-compartments: granular component (GC), dense fibrillar component (DFC), and fibrillar center (FC). FC and DFC form a core-shell architecture and are immersed by a large GC. However, factors that mediated the formation of the three-layered architecture remain largely unknown. Here, we discovered that rRNAs have specific localizations within the nucleolus, with 28S rRNA forming assemblies surrounding the DFC. Multivalent interactions of 28S rRNA drove the formation of the hollow shell structure of DFC, which mediated the development of a three-layered structure resembling nucleolar GC-DFC-FC. Moreover, in organisms with a tripartite nucleolus, 28S rRNA has evolved to acquire a higher degree of multivalency. Our data implies that the emergence of multivalency of 28S rRNA facilitates the transition of bipartite to tripartite nucleolus.

cell biology↗

bioRxiv2024

PIGOME: An Integrated and Comprehensive Multi-omics Database for Pig Functional Genomics Studies

In addition to being a major source of animal protein, pigs are important model for the study of development and diseases in humans. During the past two decades, thousands of high-throughput sequencing studies in pigs have been performed using a variety of tissues from different breeds and developmental stages. However, the multi-omics database specifically used for pig functional genomic research is still limited. Here, we present a user-friendly database of pig multi-omics named PIGOME. PIGOME contains seven types of pig omics datasets, including whole-genome sequencing, RNA-seq, miRNA-seq, ChIP-seq, ATAC-seq, bisulfite-seq, and MeRIP-seq, from 6,901 samples and 392 projects with manually curated metadata, integrated gene annotation, and quantitative trait locus information. Furthermore, various explore and browse functions have been established for user-friendly access to omics information. PIGOME implemented several tools to visualize genomic variants, gene expression, and epigenetic signals of a given gene in the pig genome, enabling efficient exploration of spatial-temporal expression/epigenetic pattern, function, regulatory mechanism, and associated economic traits. Collectively, PIGOME provides valuable resources for pig breeding and is helpful for human biomedical research. PIGOME is available at https://pigome.com.

bioinformatics↗

bioRxiv2024

Impaired central pattern generators due to abnormal EPHA4 signaling leads to idiopathic scoliosis

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we firstly reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings strongly suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.

genetics↗