FoxP1 Stimulates Angiogenesis by Repressing the Inhibitory Guidance Protein Semaphorin 5B in Endothelial Cells

Grundmann, Sebastian; Christian, Lindmayer; Hans, Felix Patricius; Hoefer, Imo E.; Helbing, Thomas; Pasterkamp, Gérard; Bode, Christoph; Kleijn, Dominique P.V. de; Moser, Martin

doi:10.1371/journal.pone.0070873

Cited by 31 publications

(28 citation statements)

References 32 publications

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“…The dynamic effect of rs7632505 on CHD may be explained by the inhibitory effect of SEMA5B on angiogenesis which is related to aging process (Lähteenvuo and Rosenzweig, 2012 ) and is purported to be involved in atherosclerosis and other CVDs (Khurana et al, 2005 ; Deveza et al, 2012 ). SEMA5B is a member of the phylogenetically conserved class 5 semaphorins that all contain a characteristic Sema domain along with thrombospondin repeats (Adams et al, 1996 ) and is functionally important for angiogenesis (Iruela-Arispe et al, 1999 ; Chen et al, 2000 ; Grundmann et al, 2013 ). The moderate expression of SEMA5B is detected in multiple tissues including heart and brain (Nagase et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Kernogitski

Kulminskaya

et al. 2016

Front. Genet.

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Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.

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Section: Discussionmentioning

confidence: 99%

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Kernogitski

Kulminskaya

et al. 2016

Front. Genet.

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“…This gene network may provide a clue to delineate the Foxp1 targets that modulate the morphogenesis of cortical neurons. In addition, a recent study found that FoxP1 stimulates angiogenesis by repressing semaphorin 5B (Sema5B) [ 59 ]. Since Sema5B is an inhibitory guidance cue for neuronal axons and is expressed in the cerebral cortex [ 60 , 61 ], this finding presents a possibility that Sema5B may be a target gene of Foxp1 for regulating the cortical development.…”

Section: Discussionmentioning

confidence: 99%

Foxp1 Regulates Cortical Radial Migration and Neuronal Morphogenesis in Developing Cerebral Cortex

Xiao

Fröhlich

et al. 2015

PLoS ONE

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FOXP1 is a member of FOXP subfamily transcription factors. Mutations in FOXP1 gene have been found in various development-related cognitive disorders. However, little is known about the etiology of these symptoms, and specifically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders.

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“…For example, FOXP1 promotes angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells. 31 Moreover, FOXP1 is upregulated in endothelial cells, smooth muscle cells, macrophages, and T cells of atherosclerotic plaque and is involved in the formation of stable plaques. 32 As another member of the FOXP family, FOXP2 plays an important role in the development of language.…”

Section: Introductionmentioning

confidence: 99%

circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways

Zhao

Liu

et al. 2018

Molecular Therapy - Nucleic Acids

100

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Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

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FoxP1 Stimulates Angiogenesis by Repressing the Inhibitory Guidance Protein Semaphorin 5B in Endothelial Cells

Cited by 31 publications

References 32 publications

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Foxp1 Regulates Cortical Radial Migration and Neuronal Morphogenesis in Developing Cerebral Cortex

circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways

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