Biology subjects

Lee, S.

Publications and source records attributed to Lee, S..

At least 613 records · Page 34Linked to original sources

bioRxiv2020

Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

Background Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance have not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.Methods The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays.Results Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.Conclusion ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.Competing Interest StatementDr. Rachel Schiff receives research funding from AstraZeneca, GlaxoSmithKline, Gilead Sciences, and PUMA Biotechnology, outside of this project; and is a consulting/advisory committee member for Macrogenics, and Eli Lilly. The other coauthors do not have competing financial interests.AbbreviationsABCATP-binding cassetteAIsaromatase inhibitorsBiFCBimolecular Fluorescence ComplementationCCDC170coiled-coil domain containing 170CSScharcoal-stripped serumΔCCDC170truncated CCDC170 proteinsE2estradiolERestrogen receptorFDAFood and Drug Administration4-OHT4-hydroxytamoxifenORFopen reading frameRPPAReverse phase protein array analysisSERDsselective ER down-regulatorsSERMsselective ER modulatorssiRNAsmall interfering RNASMCstructural maintenance of chromosomesTPERTissue Protein Extraction ReagentView Full Text

cancer biology↗

bioRxiv2020

Intra-session test-retest reliability of functional connectivity in infants

Resting functional MRI studies of the infant brain are increasingly becoming an important tool in developmental neuroscience. Whereas the test-retest reliability of functional connectivity (FC) measures derived from resting fMRI data have been characterized in the adult and child brain, similar assessments have not been conducted in infants. In this study, we examined the intra-session test-retest reliability of FC measures from 119 infant brain MRI scans from four neurodevelopmental studies. We investigated edge-level and subject-level reliability within one MRI session (between and within runs) measured by the Intraclass correlation coefficient (ICC). First, using an atlas-based approach, we examined whole-brain connectivity as well as connectivity within two common resting fMRI networks - the default mode network (DMN) and the sensorimotor network (SMN). Second, we examined the influence of run duration, study site, and scanning manufacturer (e.g., Philips and General Electric) on ICCs. Lastly, we tested spatial similarity using the Jaccard Index from networks derived from independent component analysis (ICA). Consistent with resting fMRI studies from adults, our findings indicated poor edge-level reliability (ICC = 0.14 - 0.18), but moderate-to-good subject-level intra-session reliability for whole-brain, DMN, and SMN connectivity (ICC = 0.40 - 0.78). We also found significant effects of run duration, site, and scanning manufacturer on reliability estimates. Some ICA-derived networks showed strong spatial reproducibility (e.g., DMN, SMN, and Visual Network), and were labelled based on their spatial similarity to analogous networks measured in adults. These networks were reproducibly found across different study studies. However, other ICA-networks (e.g. Executive Control Network) did not show strong spatial reproducibility, suggesting that the reliability and/or maturational course of functional connectivity may vary by network. In sum, our findings suggest that developmental scientist may be on safe ground examining the functional organization of some major neural networks (e.g. DMN and SMN), but judicious interpretation of functional connectivity is essential to its ongoing success. HighlightsO_LIInfant functional connectivity (FC) shows poor edge-level reliability (ICCs) C_LIO_LIHowever, subject-level infant FC estimates show good-to-excellent ICCs C_LIO_LISpatial reproducibility is better for some resting networks (DMN, SMN) than others (ECN) C_LIO_LIReliability estimates differ across study site and MRI scanner C_LIO_LIConclusion - Infant FC can be a reliable measurement, but judicious use is needed C_LI

bioinformatics↗

bioRxiv2020

An implant for long-term cervical vagus nerve stimulation in mice

Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity and atherosclerosis. Many of these diseases have well-established mouse models, but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic therapy remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for across-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or behaving mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing. Overall, 60-90% of implants produced stimulus-evoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4- to 6-week-old implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provides a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

bioRxiv2020

Allelic Variation of MYB10 is the Major Force Controlling Natural Variation of Skin and Flesh Color in Strawberry (Fragaria spp.) fruit

Anthocyanins are the principal color-producing compounds synthesized in developing fruits of strawberry (Fragaria spp.). Substantial natural variation in color have been observed in fruits of diploid and octoploid accessions, resulting from distinct accumulation and distribution of anthocyanins in fruits. Anthocyanin biosynthesis is controlled by a clade of R2R3 MYB transcription factors, among which MYB10 has been shown as the main activator in strawberry fruit. Here, we show that MYB10 mutations cause most of the anthocyanin variation observed in diploid woodland strawberry (F. vesca) and octoploid cultivated strawberry (F. xananassa). Using a mapping-by-sequencing approach, we identified a gypsy-transposon insertion in MYB10 that truncates the protein and knocks out anthocyanin biosynthesis in a white-fruited F. vesca ecotype. Two additional loss-of-function MYB10 mutations were identified among geographically diverse white-fruited F. vesca ecotypes. Genetic and transcriptomic analyses in octoploid Fragaria spp. revealed that FaMYB10-2, one of three MYB10 homoeologs identified, residing in the F. iinumae-derived subgenome, regulates the biosynthesis of anthocyanins in developing fruit. Furthermore, independent mutations in MYB10-2 are the underlying cause of natural variation in fruit skin and flesh color in octoploid strawberry. We identified a CACTA-like transposon (FaEnSpm-2) insertion in the MYB10-2 promoter of red-fleshed accessions that was associated with enhanced expression and anthocyanin accumulation. Our findings suggest that putative cis regulatory elements provided by FaEnSpm-2 are required for high and ectopic MYB10-2 expression and induction of anthocyanin biosynthesis in fruit flesh. We developed MYB10-2 (sub-genome) specific DNA markers for marker-assisted selection that accurately predicted anthocyanin phenotypes in octoploid segregating populations.

plant biology↗

bioRxiv2020

SARS-CoV-2-specific T cells exhibit unique features characterized by robust helper function, lack of terminal differentiation, and high proliferative potential

Convalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can homeostatically proliferate, and can persist for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.

immunology↗

bioRxiv2020

Peripheral blood microbial signatures in COPD

BackgroundThe human microbiome has a role in the development of human diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. Specifically, the blood microbiome, once believed sterile, may be a surrogate for some lung and gut microbial characteristics. We sought associations between the blood microbiome and lung-relevant host factors. MethodsBased on reads not mapped to the human genome, we detected microbial nucleic acid signatures in peripheral blood RNA-sequencing for 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the GATK microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. ResultsThe four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. We observed associations between exacerbation phenotypes and the relative abundance of Staphylococcus, Acidovorax and Cupriavidus. The genus Flavobacterium was associated with emphysema and change in emphysema. Our host-microbiome interaction analysis revealed clustering of genera associated with emphysema, systemic inflammation, airway remodeling and exacerbations, through links to lung-relevant host pathways. ConclusionsThis study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between the systemic microbial populations and lung disease severity may inform novel interventions and aid in the understanding of exacerbation phenotypes.

genomics↗

bioRxiv2020

Deep Metric Learning Network using Proxies for Chromosome Classification and Retrieval in Karyotyping Test

In karyotyping, the classification of chromosomes is a tedious, complicated, and time-consuming process. It requires extremely careful analysis of chromosomes by well-trained cytogeneticists. To assist cytogeneticists in karyotyping, we introduce Proxy-ResNeXt-CBAM which is a metric learning based network using proxies with a convolutional block attention module (CBAM) designed for chromosome classification. RexNeXt-50 is used as a backbone network. To apply metric learning, the fully connected linear layer of the backbone network (ResNeXt-50) is removed and is replaced with CBAM. The similarity between embeddings, which are the outputs of the metric learning network, and proxies are measured for network training. Proxy-ResNeXt-CBAM is validated on a public chromosome image dataset, and it achieves an accuracy of 95.86%, a precision of 95.87%, a recall of 95.9%, and an F-1 score of 95.79%. Proxy-ResNeXt-CBAM which is the metric learning network using proxies outperforms the baseline networks. In addition, the results of our embedding analysis demonstrate the effectiveness of using proxies in metric learning for optimizing deep convolutional neural networks. As the embedding analysis results show, Proxy-ResNeXt-CBAM obtains a 94.78% Recall@1 in image retrieval, and the embeddings of each chromosome are well clustered according to their similarity.

bioengineering↗

bioRxiv2020

The dorsal and ventral default mode networks are dissociably modulated by the valence and vividness of imagined events

Recent work has shown that the brains default mode network (DMN) is active when people imagine the future. Here we test whether future imagination can be decomposed into two dissociable psychological processes linked to different subcomponents of the DMN. While measuring brain activity with fMRI as subjects imagine future events, we manipulate the vividness of these events to modulate the demands for scene construction, and we manipulate the valence of these events to modulate the demands for evaluation. We found that one subcomponent of the DMN, the ventral DMN or medial temporal lobe subsystem, responds to the vividness but not the valence of imagined events. In contrast, another subcomponent, the dorsal or core DMN, responds to the valence but not the vividness of imagined events. This separate modifiability of different subcomponents of the DMN by vividness and valence provides strong evidence for a neurocognitive dissociation between (1) the construction of novel, imagined scenes from individual components from memory and (2) the evaluation of these constructed events as desirable or undesirable. Significance StatementPrevious work has suggested that imagination may depend on separate neural networks involved in the construction and evaluation of imagined future events. This study provides strong neural evidence for this dissociation by demonstrating that two components of the brains default mode network (DMN) uniquely and specifically respond to different aspects of imagination. The vividness of imagined events modulates the ventral DMN, but not the dorsal DMN, while the valence of imagined events modulates the dorsal DMN, but not the ventral DMN. This supports the dissociable engagement of these sub-networks in constructing and evaluating imagined future events.

neuroscience↗

bioRxiv2020

Algorithmic Assessment of Missense Mutation Severity in the Von-Hippel Lindau Protein

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.View Full Text

pathology↗

bioRxiv2020

Distinct neural encoding of context-dependent error signals and context-dependent changes in behavior during adaptive learning

Effective learning requires using errors in a task-dependent manner, for example adjusting to errors that result from unpredicted environmental changes but ignoring errors that result from environmental stochasticity. Where and how the brain represents errors in a task-dependent manner and uses them to guide behavior are not well understood. We imaged the brains of human participants performing a predictive-inference task with two conditions that had different sources of errors. Their performance was sensitive to this difference, including more choice switches after fundamental changes versus stochastic fluctuations in reward contingencies. Using multi-voxel pattern classification, we identified task-dependent representations of error magnitude and past errors in posterior parietal cortex. These representations were distinct from representations of the resulting behavioral adjustments in dorsomedial frontal, anterior cingulate, and orbitofrontal cortex. The results provide new insights into how the human brain represents errors in a task-dependent manner and guides subsequent adaptive behavior.

neuroscience↗

bioRxiv2020

Neural Correlates of Value Are Intrinsically History Dependent

The authors have withdrawn their manuscript since they no longer stand by the results reported in this preprint. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗

bioRxiv2020

Unsupervised cluster analysis of SARS-CoV-2 genomes reflects its geographic progression and identifies distinct genetic subgroups of SARS-CoV-2 virus

Over 10,000 viral genome sequences of the SARS-CoV-2 virus have been made readily available during the ongoing coronavirus pandemic since the initial genome sequence of the virus was released on the open access Virological website (http://virological.org/) early on January 11. We utilize the published data on the single stranded RNAs of 11, 132 SARS-CoV-2 patients in the GISAID (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) database, which contains fully or partially sequenced SARS-CoV-2 samples from laboratories around the world. Among many important research questions which are currently being investigated, one aspect pertains to the genetic characterization/classification of the virus. We analyze data on the nucleotide sequencing of the virus and geographic information of a subset of 7, 640 SARS-CoV-2 patients without missing entries that are available in the GISAID database. Instead of modelling the mutation rate, applying phylogenetic tree approaches, etc., we here utilize a model-free clustering approach that compares the viruses at a genome-wide level. We apply principal component analysis to a similarity matrix that compares all pairs of these SARS-CoV-2 nucleotide sequences at all loci simultaneously, using the Jaccard index (Jaccard, 1901; Tan et al., 2005; Prokopenko et al., 2016; Schlauch et al., 2017). Our analysis results of the SARS-CoV-2 genome data illustrates the geographic and chronological progression of the virus, starting from the first cases that were observed in China to the current wave of cases in Europe and North America. This is in line with a phylogenetic analysis which we use to contrast our results. We also observe that, based on their sequence data, the SARS-CoV-2 viruses cluster in distinct genetic subgroups. It is the subject of ongoing research to examine whether the genetic subgroup could be related to diseases outcome and its potential implications for vaccine development.

genomics↗

bioRxiv2020

Impaired hand dexterity function in a non-human primate model with chronic Parkinson's disease

Symptoms of Parkinsons disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed an alteration in Parkinsonian tremor symptoms, loss of dopaminergic neuron, and positron emission tomography (PET) imaging of dopamine transporters (DAT) in these models. HDT latency significantly increased in NHP-PD models. In addition, a significant inverse correlation between HDT and DAT was identified, but no local bias was found. The correlation with intention tremor symptoms was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.

neuroscience↗

bioRxiv2020

HiTea: a computational pipeline to identify non-reference transposable element insertions in Hi-C data

Hi-C is a common technique for assessing three-dimensional chromatin conformation. Recent studies have shown that long-range interaction information in Hi-C data can be used to generate chromosome-length genome assemblies and identify large-scale structural variations. Here, we demonstrate the use of Hi-C data in detecting mobile transposable element (TE) insertions genome-wide. Our pipeline HiTea (Hi-C based Transposable element analyzer) capitalizes on clipped Hi-C reads and is aided by a high proportion of discordant read pairs in Hi-C data to detect insertions of three major families of active human TEs. Despite the uneven genome coverage in Hi-C data, HiTea is competitive with the existing callers based on whole genome sequencing (WGS) data and can supplement the WGS-based characterization of the TE insertion landscape. We employ the pipeline to identify TE insertions from human cell-line Hi-C samples. HiTea is available at https://github.com/parklab/HiTea and as a Docker image.

bioinformatics↗

bioRxiv2020

Ontogeny and function of the circadian clock in intestinal organoids

Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed molecular mechanisms regulating circadian physiology of the intestine remain largely unknown. The lack of appropriate human model systems that enable organ- and/or diseasespecific interrogation of clock functions is a major obstacle hindering advancements of translational applications using chronotherapy. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids (HIEs) possess robust circadian rhythms, and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses. RNA-Seq data show ~4% of genes are rhythmically expressed in HIEs. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids. Importantly, the observed circadian time-dependent necrotic cell death response is abolished in both mouse enteroids and human intestinal organoids (HIOs) lacking robust circadian rhythms. Our findings uncover robust functions of circadian rhythms regulating critical clock-controlled genes (CCGs) in human enteroids governing organism-specific, circadian phasedependent necrotic cell death responses. Our data highlight unique differences between mouse and human enteroids, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications.

molecular biology↗

bioRxiv2020

Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics

Enhancer-promoter dynamics are crucial for the spatiotemporal control of gene expression, but it remains unclear whether these dynamics are controlled by chromatin regulators, such as the nucleosome remodelling and deacetylase (NuRD) complex. The NuRD complex binds to all active enhancers to modulate transcription and here we use Hi-C experiments to show that it blurs TAD boundaries and increases the proximity of intermediate-range (~1 Mb) genomic sequences and enhancer-promoter interactions. To understand whether NuRD alters the dynamics of 3D genome structure, we developed an approach to segment and extract key biophysical parameters from 3D single-molecule trajectories of the NuRD complex determined using live-cell imaging. Unexpectedly, this revealed that the intact NuRD complex decompacts chromatin structure and makes NuRD-bound enhancers move faster, increasing the overall volume of the nucleus that these key regulatory regions explore. Interestingly, we also uncovered a rare fast-diffusing state of NuRD bound enhancers that exhibits directed motion. The NuRD complex reduces the amount of time that enhancers remain in this fast-diffusing state, which we propose might otherwise re-organise enhancer-promoter proximity. Thus, we uncover an intimate connection between a chromatin remodeller and the spatial dynamics of the local regions of the genome to which it binds.

cell biology↗

bioRxiv2020

Local and global dichotomic dysfunction in resting and evoked functional connectivity precedes tauopathy

Functional network activity alterations are one of the earliest hallmarks of Alzheimers disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.

neuroscience↗

bioRxiv2020

A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina

Connective tissue growth factor (CTGF) or CCN2 is a matricellular protein essential for normal embryonic development and tissue repair. CTGF exhibits cell- and context-dependent activities, but the CTGF function in vascular development and permeability barrier is not known. Here we show that endothelial cells (ECs) are one of the major cellular sources of CTGF in the developing and adult retinal vasculature. Mice lacking CTGF expression either globally or specifically in ECs exhibit impaired vascular cell growth and morphogenesis, and blood barrier breakdown. The global molecular signature of CTGF includes cytoskeletal and extracellular matrix protein, growth factor, and transcriptional co-regulator genes such as yes-associated protein (YAP). YAP, itself a transcriptional activator of the CTGF gene, mediates several CTGF-controlled angiogenic and barriergenic transcriptional programs. Re-expression of YAP rescues, at least partially, angiogenesis and barriergenesis in CTGF mutant mouse retinas. Thus, the CTGF-YAP angiomodulatory pathway is critical for vascular development and barrier function.

developmental biology↗