Biology subjects

Mani, A.

Publications and source records attributed to Mani, A..

18 recordsLinked to original sources

bioRxiv2026

Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes

Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1 SREBP2 activation, impaired autophagy, and NF-kB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2 dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease.

genetics↗

bioRxiv2026

Deletion of endothelial KLF4 as a model for preeclampsia

Preeclampsia (PE), or gestational hypertension, affects around 5% of pregnancies and leads to approximately 70,000 maternal and 500,000 fetal deaths per year worldwide, with increased cardiovascular and metabolic disease in survivors. PE is associated with elevated circulating levels of the alternative splice isoform of VEGF receptor 1 (sFlt1), defects in placental vasculature, kidney damage and, in severe disease, fetal growth restriction. Current mouse models induce PE via direct expression of sFlt1 or elevation of blood pressure, which bypass the natural risk factors for human disease, such as age, obesity, hypertension and diabetes. These risk factors have in common reduced expression of Kruppel-like factors 2 and 4 (KLF2/4), the endothelial transcription factors that protect against cardiovascular disease. We now report that inducible deletion of KLF4 in maternal endothelium (KLF4iECKO) results in gestational hypertension, elevated sFlt1, defective placental vasculature, kidney damage and fetal growth restriction. KLF4iECKO may thus serve as a mouse PE model suitable for mechanistic analysis and screening of treatments that address upstream risk factors.

cell biology↗

bioRxiv2025

Latrophilin-2 Orchestrates Endothelial Flow-Mediated Smad1/5 Activation via Endoglin and Shank3

Fluid shear stress (FSS) from blood flow critically determines vascular morphology and function. FSS activates the Smad1/5 pathway maximally at physiological FSS through the BMP9/10 receptors Alk1 and Endoglin to promote vascular stability. We now report that the adhesion G protein-coupled receptor Latrophilin-2 (Lphn2), which mediates flow activation of the canonical junctional complex, is required for flow-mediated Smad1/5 activation in endothelial cells. Lphn2 physically associates with Endoglin and is required for Smad1/5 activation by FSS but not soluble BMP9. This regulation is independent of G-proteins but requires Lphn2s C-terminal PDZ binding motif. Endothelial-specific Lphn2 knockout reduces Smad1/5 activation in mice. In zebrafish embryos, loss of flow or Lphn2 knockout similarly reduced endothelial Smad1/5 activation, with no additive effect, indicating that Lphn2 mediates flow-induced activation in vivo. APEX2 proximity labeling revealed that the PDZ domain-containing scaffold protein Shank3 associated with Lphn2 under flow. Shank3 knockdown blocked flow-induced Smad1/5 activation in vitro and Shank3 global knockout mice exhibited reduced endothelial nuclear Smad1/5 and increased susceptibility to arteriovenous malformations. Lphn2 thus mediates flow-induced Smad1/5 activation and vessel stabilization through the scaffold protein Shank3, independently of G proteins. Together with the accompanying paper on Notch1, we conclude that Lphn2 confers FSS sensitivity to three of the major FSS pathways via distinct mechanisms.

cell biology↗

bioRxiv2025

SARM1 base-exchange inhibitors induce SARM1 activation and neurodegeneration at low doses

SARM1 has emerged as a promising therapeutic target in neurology due to its central role in axonal degeneration and its amenability to different modes of small molecule inhibition. One chemical approach to modulate SARM1 involves orthosteric inhibition via a SARM1-mediated base-exchange reaction between a small molecule and nicotinamide adenine dinucleotide (NAD+), the substrate of SARM1, to generate the active inhibitor. Here, we report that subinhibitory concentrations of SARM1 base-exchange inhibitors (BEIs) paradoxically increase SARM1 activity and worsen SARM1-induced cell death and neuronal damage in vitro. Low dose administration of RO-7529, a SARM1 BEI, exacerbated experimental autoimmune encephalomyelitis (EAE)-induced neurodegeneration in vivo. Our data highlight a unique pharmacological feature of SARM1 BEIs that may limit their therapeutic application in disorders associated with SARM1 activation and axonal degeneration.

neuroscience↗

bioRxiv2025

Non-invasive assessment of integrated cardiorespiratory network dynamics after physiological stress in humans

BackgroundPhysiological variables provide critical insights into the integrated control of the cardiorespiratory system, reflecting the bodys real-time responses to internal and external perturbations. Visualizing the exchange of information between different components of the cardiorespiratory system is beneficial for monitoring individuals in various clinical settings and extreme environments. This study aimed to develop a non-invasive method, using principles of information theory, to visualize the flow of information between physiological variables, with a focus on the integrated cardiorespiratory responses to different physiological stressors. MethodsHeart rate, respiratory rate, minute ventilation, respiratory frequency, tidal volume, capillary oxygen saturation (SpO2), end-tidal oxygen, and end-tidal carbon dioxide concentrations were recorded from 22 healthy participants. Transfer entropy, which reflects measures of causal relationships between parallel time-series, was used to compute the flow of information between cardiorespiratory signals into network maps. Network mapping was performed after rest in a control condition and following exposure to the isolated and combined effects of normobaric hypoxia (FIO2: 0.12), moderate intensity cycling exercise (100W), and overnight sleep deprivation. For each intervention, 10-minute segments of physiological signals (from minutes 5 to 15 after the commencement of hypoxia and/or exercise) were used for analysis. ResultsEach physiological stressor was associated with a distinctive pattern of information flow between physiological variables. Hypoxia led to the engagement of SpO2 a hub in the network, facilitating the exchange of information with end-tidal oxygen concentration and heart rate. Sleep deprivation was associated with a shift in the flow of information from SpO2 to other nodes, such as respiratory rate, during hypoxia. During exercise, heart rate emerged as the central node for receiving information, while SpO2 acted as the primary node disseminating information to other nodes. Increased connectivity within the networks was observed during exercise alone or when combined with other stressors. ConclusionThis non-invasive network mapping technique visualizes the interaction of various cardiorespiratory variables following exposure to physiological stressors. By mapping normative responses, this approach may help identify outliers associated with various disease states.

physiology↗

bioRxiv2024

Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions

Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs) and PlexinD1 located at cell-cell junctions mediates many of these events. But available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and G proteins may serve this role, we performed siRNA screening of G subunits and found that Gi2 and Gq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the G residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn-2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology and disease.

molecular biology↗

bioRxiv2024

The telencephalon is a neuronal substrate for systemic inflammatory responses in teleosts via polyamine metabolism

Systemic inflammation elicits sickness behaviors and fever by engaging a complex neuronal circuitry that begins in the preoptic area of the hypothalamus. Ectotherms such as teleost fish display sickness behaviors in response to infection or inflammation, seeking warmer temperatures to enhance survival via behavioral fever responses. To date, the hypothalamus is the only brain region implicated in sickness behaviors and behavioral fever in teleosts. Yet, the complexity of neurobehavioral manifestations underlying sickness responses in teleosts suggests engagement of higher processing areas of the brain. Using two in vivo models of systemic inflammation in rainbow trout, we find canonical pyrogenic cytokine responses in the hypothalamus whereas in the telencephalon il-1b and tnfa expression is decoupled from il-6 expression. Polyamine metabolism changes, characterized by accumulation of putrescine and decreases in spermine and spermidine, are recorded in the telencephalon but not hypothalamus upon systemic injection of bacteria. While systemic inflammation causes canonical behavioral fever in trout, blockade of bacterial polyamine metabolism prior to injection abrogates behavioral fever, polyamine responses and telencephalic but not hypothalamic cytokine responses. Combined, our work identifies the telencephalon as a neuronal substrate for brain responses to systemic inflammation in teleosts and uncovers the role of polyamines as critical chemical mediators in sickness behaviors. Significance StatementSystemic inflammation induces neuroimmune responses in the brain resulting in sickness behaviors and fever. In endotherms, sickness behaviors and fever are initiated in the hypothalamus but also engage a complex neuronal circuitry in higher areas of the brain. In ectotherms, only the hypothalamus has been linked to sickness behaviors and behavioral fever. Here we demonstrate that the telencephalon, a critical region of the teleost brain responsible for higher order processing, mounts pyrogenic cytokine responses to systemic inflammation in teleosts that are different from those of the hypothalamus. We identify polyamine metabolism as a core response of the teleost telencephalon to systemic inflammation and report that bacterial polyamines are triggers of behavioral fever in rainbow trout. Our work uncovers a previously unrecognized role for the telencephalon and polyamine metabolism in sickness behaviors and behavioral fever in teleosts with implications in fish health and fish conservation.

immunology↗

bioRxiv2023

A niche-adapted brain microbiome in salmonids at homeostasis

Ectotherms have long been known to have peculiar relationships with microorganisms. For instance, bacteria can be recovered from blood and internal organs of healthy teleost fish. However, until now, the presence of a microbial community in the healthy teleost brain has not been proposed. Here we report a living bacterial community in the brain of healthy salmonids. Brain bacterial loads in salmonids are comparable to those found in the spleen and 1000-fold lower than in the gut. Brain bacterial communities share >50% of their diversity with gut and blood bacterial communities. Using culturomics, we obtained 54 bacterial isolates from the brain of healthy rainbow trout. Comparative genomics uncovered unique niche adaptations associated with brain colonization and polyamine biosynthesis. In a natural system, salmonid brain microbiomes shift with the host life cycle, becoming dysbiotic in reproductively mature Chinook salmon, a species that undergoes reproductive death. Our study redefines the relationship between the teleost brain and bacterial microbiomes under physiological conditions. We posit that this symbiosis may endow salmonids with a direct mechanism to sense and respond to environmental microbes. One-Sentence SummarySalmonids have a brain-adapted, resident bacterial community

microbiology↗

bioRxiv2023

Secretory IgM (sIgM) is an ancient master regulator of microbiota homeostasis and metabolism

The co-evolution between secretory immunoglobulins (sIgs) and microbiota began with the emergence of IgM over half a billion years ago. Yet, IgM function in vertebrates is mostly associated with systemic immunity against pathogens. sIgA and sIgT are the only sIgs known to be required in the control of microbiota homeostasis in warm- and cold-blooded vertebrates respectively. Recent studies have shown that sIgM coats a large proportion of the gut microbiota of humans and teleost fish, thus suggesting an ancient and conserved relationship between sIgM and microbiota early in vertebrate evolution. To test this hypothesis, we temporarily and selectively depleted IgM from rainbow trout, an old bony fish species. IgM depletion resulted in a drastic reduction in microbiota IgM coating levels and losses in gutassociated bacteria. These were accompanied by bacterial translocation, severe gut tissue damage, inflammation and dysbiosis predictive of metabolic shifts. Furthermore, depletion of IgM resulted in body weight loss and lethality in an experimental colitis model. Recovery of sIgM to physiological levels restores tissue barrier integrity, while microbiome homeostasis and their predictive metabolic capabilities are not fully restituted. Our findings uncover a previously unrecognized role of sIgM as an ancient master regulator of microbiota homeostasis and metabolism and challenge the current paradigm that sIgA and sIgT are the key vertebrate sIgs regulating microbiome homeostasis. One-Sentence SummaryIgM, the most ancient and conserved immunoglobulin in jawed vertebrates, is required for successful symbiosis with the gut microbiota.

immunology↗

bioRxiv2022

Taxonomic practice, creativity, and fashion: What's in a spider name?

Theres a secret pleasure in naming new species. Besides traditional etymologies recalling the sampling locality, habitat, or morphology of the species, etymologies may be tributes to some meaningful person (for example, the species collector, the authors husband or wife, or a celebrity), pop culture references, and even exercises of enigmatography. The possibility of choosing witty or even playful names for new species departs from the otherwise impersonal and old-fashioned writing style thats common in taxonomic papers; but, how has the descriptors choice for specific etymologies changed over the 300+ years since the introduction of the Linnaean binomial system of nomenclature? Using an unprecedented dataset of 48,464 etymologies (all valid species and subspecies of spiders described between 1757 and May 2020), we tested the hypothesis that species names given by taxonomists are deeply influenced by their cultural background. In particular, we asked whether naming practices change through space (continent in which the species was found) or have changed through time (year of description). We observed spatial and temporal differences in the way taxonomists name new species. In absolute terms, etymologies referring to morphology were the most frequently used. In relative terms, however, references to morphology peaked in 1850-1900 and then began to decline, with a parallel increase in etymologies dedicated to people and geography. Currently, these are the most widely used, with [~]38% of all etymologies of spider species described in the last ten years referring to geography, [~]25% to people, and [~]25% to morphology. Interestingly, there has been a dramatic increase in etymologies referring to pop culture and other cultural aspects in the last two decades, especially in Europe and the Americas. While such fashionable names often carry little or no biological information regarding the species itself, they help give visibility to the science of taxonomy, a discipline currently facing a profound crisis within academia. Taxonomy is among the most unchanged disciplines across the last centuries in terms of background, tools, rules, and writing style; but our analysis suggests that taxonomists remain deeply influenced by their living time and space.

scientific communication and education↗

bioRxiv2021

A retinal circuit that vetoes optokinetic responses to fast visual motion

Optokinetic nystagmus (OKN) complements the vestibulo-ocular reflex (VOR) to stabilize the retinal image during head rotation. OKN is driven by the ON direction-selective ganglion cells (ON DSGCs), a rare class of retinal output neuron that encodes both the direction and speed of global retinal slip. The cells and synaptic circuits that give ON DSGCs their directional tuning are well known, but those dictating their slow-speed preference (and thus OKNs) remain enigmatic. Here, we probe this circuit through patch recordings, functional imaging, genetic manipulation, and serial electron microscopic reconstruction in mouse retina. We confirm earlier evidence that feedforward glycinergic inhibition is the main suppressor of ON DSGC responses to fast motion and reveal a surprising source for this inhibition [boxh] the VGluT3 amacrine cell, a retinal interneuron that releases both glycine and glutamate, exciting some neurons and inhibiting others. We find that VGluT3 cells respond robustly to fast global motion and that their output reaches most RGC types, as well as a diverse group of amacrine and bipolar cells. They enhance the response of ON-OFF DSGCs to fast motion, while suppressing it in ON DSGCs. Together, our results identify a novel role for VGluT3 cells, limiting the range of retinal slip speeds that drive image-stabilizing eye movements. More broadly, they suggest VGluT3 cells shape the response of many RGCs and amacrine cells to fast motion.

neuroscience↗

bioRxiv2021

Unified classification of mouse retinal ganglion cells using function, morphology, and gene expression

Classification and characterization of neuronal types are critical for understanding their function and dysfunction. Neuronal classification schemes typically rely on measurements of electrophysiological, morphological, and molecular features, but aligning such datasets has been challenging. Here, we present a unified classification of mouse retinal ganglion cells (RGCs), the sole retinal output neurons. We used visually-evoked responses to classify 1859 mouse RGCs into 42 types. We also obtained morphological or transcriptomic data from subsets and used these measurements to align the functional classification to publicly available morphological and transcriptomic data sets. We created an online database that allows users to browse or download the data and to classify RGCs from their light responses using a machine learning algorithm. This work provides a resource for studies of RGCs, their upstream circuits in the retina, and their projections in the brain, and establishes a framework for future efforts in neuronal classification and open data distribution.

neuroscience↗

bioRxiv2021

cellxgene: a performant, scalable exploration platform for high dimensional sparse matrices

Quickly and flexibly exploring high-dimensional datasets, such as scRNAseq data, is underserved but critical for hypothesis generation, dataset annotation, publication, sharing, and community reuse. cellxgene is a highly generalizable, web-based interface for exploring high dimensional datasets along categorical, continuous and spatial dimensions, as well as feature annotation. cellxgene is differentiated by its ability to performantly handle millions of observations, and bridges a critical gap by enabling computational and experimental biologists to iteratively ask questions of private and public datasets. In doing so, cellxgene increases the utility and reusability of datasets across the single-cell ecosystem. The codebase can be accessed at https://github.com/chanzuckerberg/cellxgene. For questions and inquiries, please contact cellxgene@chanzuckerberg.com.

systems biology↗

bioRxiv2020

Effects of ploidy and salmonid alphavirus infection on the skin and gill microbiome of Atlantic salmon (Salmo salar)

The microbial communities that live in symbiosis with the mucosal surfaces of animals provide the host with defense strategies against pathogens. These microbial communities are largely shaped by the environment and the host genetics. Triploid Atlantic salmon (Salmo salar) are being considered for aquaculture as they are reproductively sterile and thus cannot contaminate the natural gene pool. It has not been previously investigated how the microbiome of triploid salmon compares to that of their diploid counterparts. In this study, we compare the steady-state skin and gill microbiome of both diploid and triploid salmon, and determine the effects of salmonid alphavirus 3 experimental infection on their microbial composition. Our results show limited differences in the skin-associated microbiome between triploid and diploid salmon, irrespective of infection. In the gills, we observed a high incidence of the bacterial pathogen Candidatus Branchiomonas, with higher abundance in diploid compared to triploid control fish. Diploid salmon infected with SAV3 showed greater histopathological signs of epitheliocystis compared to controls, a phenomenon not observed in triploid fish. Our results indicate that ploidy can affect the alpha diversity of the gills but not the skin-associated microbial community. Importantly, during a natural outbreak of Branchiomonas sp. the gill microbiome of diploid Atlantic salmon became significantly more dominated by this pathogen than in triploid animals. Thus, our results suggest that ploidy may play a role on Atlantic salmon gill health and provide insights into co-infection with SAV3 and C. Branchiomonas in Atlantic salmon.

microbiology↗

bioRxiv2020

Dyrk1b is a key Regulatory Kinase Integrating Fgf, Shh and mTORC1 signaling in Skeletal Muscle Development and Homeostasis

The advent of human genetics has provided unprecedented opportunities for discovery of novel disease pathways. Mutations in DYRK1B have been associated with metabolic syndrome and sarcopenic obesity in humans, underscoring the critical role of the encoded protein in skeletal muscle development and homeostasis. By the novel creation of Dyrk1b knockout zebrafish models we demonstrate that Dyrk1b kinase activity is critical for specification of the paraxial myoD. Mechanistically, Dyrk1b mediates and amplifies Fgf signaling in the paraxial domain by the transcriptional suppression of its negative feedback inhibitor sprouty1. In the adaxial myoD domain, Dyrk1b amplifies Shh signaling and partially rescues defects caused by its disruption. The investigations of C2C12 terminal differentiation revealed that Dyrk1b also plays a critical role in myofiber fusion. Combined biochemical and proteomic analysis of C2C12 myoblasts undergoing differentiation showed that Dyrk1b kinase activation is induced by shh inhibition, and triggers differentiation by inhibiting mTOR, subsequent upregulation of 4e-bp1 and induction of autophagy. In conclusion, we demonstrate that Dyrk1b plays a critical role in sustaining myocyte specification and differentiation by integrating Fgf, Shh and mTORC1 signaling pathways.

developmental biology↗

bioRxiv2019

Inhibition of Microbial Beta-Glucuronidase Does Not Prevent Breast Carcinogenesis in the Polyoma Middle T Mouse

PurposeTo demonstrate whether inhibition of intestinal microbial beta ({beta})-glucuronidase (BGUS) abrogates tumor formation in a MMTV-PyMT mouse breast cancer model.\n\nMethodsFemale MMTV-PyMT heterozygote mice (4 weeks old) were randomized to oral gavage with vehicle or UNC10201652 (20 g/day), a microbial BGUS inhibitor, for 9 weeks. The entire animal carcass was assessed for tumor deposits by histology and immunohistochemical staining for tumor (Ki67, PCNA) and breast specific (ER, PR, Cyclin D1, aSMA, Integrin {beta}1) markers.\n\nResultsThe MMTV-PyMT breast pathology in our study simulates prior published reports of tumor incidence and aggressiveness. There was no significant difference in the tumor histology, number of tumors (lesions), and patterns of spread of tumors in the UNC10201652 versus the vehicle treated mice. Similarly, there were no significant differences in the semi-quantitative scores for expression of ER, PR, Ki67, PCNA, or Integrin {beta}1. There were also no major differences seen in qualitative screening of Cyclin D1 and aSMA.\n\nConclusionsMMTV-PyMT mice administered UNC10201652, when compared to vehicle treated mice, show a similar abundance of breast tumor (and tumor initiating) lesions ranging from hyperplasia to frank carcinoma. There is a trend, however small, that the incidence of hyperplastic and adenomas may be decreased in UNC10201652 treated mice. Further refined dosing strategies in MMTV-PyMT are planned to clarify its biological significance. To our knowledge this is the first report of use of any BGUS inhibitor in chemoprevention of breast tumors using a genetic model simulating human breast cancer.

cancer biology↗

bioRxiv2018

Engineered orthogonal quorum sensing systems for synthetic gene regulation

Gene regulators that are controlled by membrane-permeable compounds called Homoserine lactones (HSLs) have become popular tools for building synthetic gene networks that coordinate behaviors across populations of engineered bacteria. Synthetic HSL-signaling systems are derived from natural DNA and protein elements from microbial quorum signaling pathways. Crosstalk, where a single HSL can activate multiple regulators, can lead to faults in networks composed of parallel signaling pathways. Here, we report an investigation of quorum sensing components to identify synthetic pathways that exhibit little to no crosstalk in liquid and solid cultures. In previous work, we characterized the response of a single regulator (LuxR) to ten distinct HSL-synthase enzymes. Our current study determined the responses of five different regulators (LuxR, LasR, TraR, BjaR, and AubR) to the same set of synthases. We identified two sets of orthogonal synthase-regulator pairs (BjaI/BjaR + EsaI/TraR and LasI/LasR + EsaI/TraR) that show little to no crosstalk when they are expressed in Escherichia coli BL21. These results expand the toolbox of characterized components for engineering microbial communities.

synthetic biology↗

bioRxiv2018

TCF7L2 Regulation of GATA6-dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia

Genetic variations in Wnt-coreceptor LRP6 and Wnt-regulated transcription factor TCF7L2 have been among the strongest genetic signals for type2 diabetes (T2DM) and coronary artery disease (CAD). Mice with a CAD-linked LRP6 mutation exhibit obstructive coronary artery disease characterized by reduced TCF7L2 expression and dedifferentiation of vascular smooth muscle cell (VSMC). While TCF7L2 maintains stemness and promotes proliferation in embryonic tissues and adult stem cells, its role and mechanisms of action in VSMC differentiation is not understood. Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of VSMCs. TCF7L2 accomplishes these effects by stabilization of GATA6 and upregulation of SM-MHC and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared to wildtype littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury induced intimal hyperplasia. These novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into poorly understood mechanisms underlying pathogenesis of intimal hyperplasia.

molecular biology↗