Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Escobedo, Noelia; Contreras, Osvaldo; Muñoz, Rosana; Farias, Marjorie; Carrasco, Héctor; Hill, Catherine M.; Tran, Uyen; Pryor, Sophie E.; Wessely, Oliver; Copp, Andrew J.; Larraı́n, Juan

doi:10.1242/dev.091173

Cited by 39 publications

(38 citation statements)

References 53 publications

(84 reference statements)

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“…S4 can cooperate with integrins in adhesion to extracellular matrix and subsequent signaling (48); however, in the context of flow signaling, our data show they clearly act on distinct pathways. S4 has been reported to interact with polarity proteins (12), to control To assess NF-κB translocation, cells were stained for p65, imaged, and analyzed as described in Methods. The translocation factor is the total nuclear p65 fluorescence relative to the total cytosolic p65 fluorescence.…”

Section: Discussionmentioning

confidence: 99%

“…They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9)(10)(11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).…”

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confidence: 88%

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Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Baeyens

Mulligan-Kehoe

Corti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

134

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Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4 −/− ) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4 −/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis. mechanotransduction | polarity | shear stress | atherosclerosis S yndecan 4 (S4) is a transmembrane heparan sulfate proteoglycan that serves as a coreceptor for extracellular matrix proteins and growth factors (1-3). S4−/− mice are viable and fertile (4, 5) but show defective wound healing consequent to impaired angiogenesis (6). They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9-11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).Atherosclerosis is an inflammatory disease of large to midsized arteries that is the major cause of illness and death in developed nations and is rapidly increasing in developing nations (14,15). It is linked to a variety of risk factors including high LDL cholesterol level and triglycerides, diabetes, smoking, hypertension, sedentary lifestyle, and inflammatory mediators. However, atherosclerotic lesions occur selectively in regions of arteries that are subject to disturbances in fluid shear stress (FSS), the frictional force flowing blood exerts on the endothelium. Regions of arteries with lower flow magnitude, flow reversal, and other complex spatial/ temporal flow patterns are predisposed to atherosclerosis. Systemic risk factors appear to synergize with local biomechanical factors in the initiation and progression of atherosclerotic lesions (16).The importance of S4 in endothelial bi...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Baeyens

Mulligan-Kehoe

Corti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

134

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“…(79) The characteristic looped tail of Vangl2 Lp/þ mice is believed to develop because of defective neural tube closure, although heterozygous mice grow to adulthood and are fertile. (63,80) This may be in part due to compensation for loss of Vangl2 function by Vangl1 in other tissue types. Vangl1 is a highly conserved, structurally similar paralogue of Vangl2, and is the only other known mammalian orthologue of Drosophila strabismus/Van Gogh.…”

Section: Discussionmentioning

confidence: 99%

Planar Cell Polarity Aligns Osteoblast Division in Response to Substrate Strain

Galea¹,

Meakin²,

Savery

et al. 2014

Journal of Bone and Mineral Research

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Exposure of bone to dynamic strain increases the rate of division of osteoblasts and also influences the directional organization of the cellular and molecular structure of the bone tissue that they produce. Here, we report that brief exposure to dynamic substrate strain (sufficient to rapidly stimulate cell division) influences the orientation of osteoblastic cell division. The initial proliferative response to strain involves canonical Wnt signaling and can be blocked by sclerostin. However, the strain-related orientation of cell division is independently influenced through the noncanonical Wnt/planar cell polarity (PCP) pathway. Blockade of Rho-associated coiled kinase (ROCK), a component of the PCP pathway, prevents strain-related orientation of division in osteoblast-like Saos-2 cells. Heterozygous loop-tail mutation of the core PCP component van Gogh-like 2 (Vangl2) in mouse osteoblasts impairs the orientation of division in response to strain. Examination of bones from Vangl2 loop-tail heterozygous mice by µCT and scanning electron microscopy reveals altered bone architecture and disorganized bone-forming surfaces. Hence, in addition to the well-accepted role of PCP involvement in response to developmental cues during skeletal morphogenesis, our data reveal that this pathway also acts postnatally, in parallel with canonical Wnt signaling, to transduce biomechanical cues into skeletal adaptive responses. The simultaneous and independent actions of these two pathways appear to influence both the rate and orientation of osteoblast division, thus fine-tuning bone architecture to meet the structural demands of functional loading. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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“…Sdc4, Vegfa, and Cp are the hub genes in the Cortex-Adult subgroup, which have been shown to execute various neurological functions. Sdc4, which encodes a cell-surface heparan sulfate proteoglycan, regulates gastrulation, neural tube closure and directed neural crest migration by wnt/PCP signaling pathway [Escobedo et al, 2013;Lin, Lu, Chen, Cheng, & Lin, 2015], Vegfa is related to Alzheimer's disease and neuronal apoptosis [Lanke, Moolamalla, Roy, & Vinod, 2018;Zhang, Wang, & He, 2018]. CP, which encodes a ceruloplasmin, is related to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

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Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Cited by 39 publications

References 53 publications

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Planar Cell Polarity Aligns Osteoblast Division in Response to Substrate Strain

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

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