AP-2β Is a Downstream Effector of PITX2 Required to Specify Endothelium and Establish Angiogenic Privilege During Corneal Development

Chen, Lisheng; Martino, Vanessa; Dombkowski, Alan A.; Williams, Trevor; West‐Mays, Judith A.; Gage, Philip J.

doi:10.1167/iovs.15-18103

Cited by 31 publications

(31 citation statements)

References 49 publications

(80 reference statements)

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“…25 We found that the compound NC- Foxc1 −/− ;NC- Foxc2 −/− mutation did not alter Pitx2 expression in the periocular mesenchyme at E11.5 (Fig. 7A); but by E14.5, levels of Pitx2, as well as its downstream effectors Dkk2 11,12 (a canonical Wnt signaling antagonist) and the AP-2β transcription factor Tfap2b, 45 were significantly lower in compound NC- Foxc1 −/− ;NC- Foxc2 −/− embryos than in control embryos (Fig. 7B).…”

Section: Resultsmentioning

confidence: 92%

Foxc1 and Foxc2 in the Neural Crest Are Required for Ocular Anterior Segment Development

Seo

Chen

Liu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeThe large Forkhead (Fox) transcription factor family has essential roles in development, and mutations cause a wide range of ocular and nonocular disease. One member, Foxc2 is expressed in neural crest (NC)-derived periocular mesenchymal cells of the developing murine eye; however, its precise role in the development, establishment, and maintenance of the ocular surface has yet to be investigated.MethodsTo specifically delete Foxc2 from NC-derived cells, conditional knockout mice for Foxc2 (NC-Foxc2−/−) were generated by crossing Foxc2F mice with Wnt1-Cre mice. Similarly, we also generated compound NC-specific mutations of Foxc2 and a closely related gene, Foxc1 (NC-Foxc1−/−;NC-Foxc2−/−) in mice.ResultsNeural crest-Foxc2−/− mice show abnormal thickness in the peripheral-to-central corneal stroma and limbus and displaced pupils with irregular iris. The neural crest-specific mutation in Foxc2 also leads to ectopic neovascularization in the cornea, as well as impaired ocular epithelial cell identity and corneal conjunctivalization. Compound, NC-specific Foxc1; Foxc2 homozygous mutant mice have more severe defects in structures of the ocular surface, such as the cornea and eyelids, accompanied by significant declines in the expression of another key developmental factor, Pitx2, and its downstream effector Dkk2, which antagonizes canonical Wnt signaling.ConclusionsThe neural crest-Foxc2 mutation is associated with corneal conjunctivalization, ectopic corneal neovascularization, and disrupted ocular epithelial cell identity. Furthermore, Foxc2 and Foxc1 cooperatively function in NC-derived mesenchymal cells to ensure proper morphogenesis of the ocular surface via the regulation of Wnt signaling. Together, Foxc2 is required in the NC lineage for mesenchymal-epithelial interactions in corneal and ocular surface development.

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Section: Resultsmentioning

confidence: 92%

Foxc1 and Foxc2 in the Neural Crest Are Required for Ocular Anterior Segment Development

Seo

Chen

Liu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…APLN/APJ receptor system plays a vital role in regulation of vascular function, including vascular tone, angiogenesis, proliferation, and permeability [20,21].In addition, APLN/APJ system also mediates the anti-in ammatory effects of 1,25(OH)2D3 by reduction of pro-in ammatory mediators and adhesion molecules in LPS-stimulated macrophages [22]. PITX2 plays an important role in regulating the differentiation of endothelium and angiogenesis [23,24].Although these studies provide insights into these biomarkers involved in regulation of cardiovascular and immune system, it is yet unknown whether these alterations can be considered as potential indicators for prevention and treatment of coronary artery damage in KD, which needs further investigations. Besides, some differences in levels of gene regulation between the RNA-seq and PCR data were noted.…”

Section: Discussionmentioning

confidence: 99%

Expression profile analysis of Differentially Expressed Genes in Human Coronary Artery Endothelial Cells Induced by Serum from Kawasaki Disease: A preliminary study

Fan

Xiao

et al. 2020

Preprint

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Background: Kawasaki disease (KD) leads to coronary artery damage and the etiology of KD is unknown. The present study was designed to explore the differentially expressed genes (DEGs) in KD serum-induced human coronary artery endothelial cells (HCAECs) by RNA-sequence (RNA-seq). Methods: HCAECs were stimulated with serum (15% (v/v)), which were collected from 20 healthy children and 20 KD patients, for 24 hours. DEGs were then detected and analyzed by RNA-seq and bioinformatics analysis. Results: The expression of SMAD1, SMAD6, CD34, CXCL1, PITX2, and APLN was validated by qPCR. 102 genes, 59 up-regulated and 43 down-regulated genes, were significantly differentially expressed in KD groups. GO enrichment analysis showed that DEGs were enriched in cellular response to cytokines, cytokine-mediated signaling pathway, and regulation of immune cells migration and chemotaxis. KEGG signaling pathway analysis showed that DEGs were mainly involved in cytokine−cytokine receptor interaction, chemokine signaling pathway, and TGF−β signaling pathway. Besides, the mRNA expression levels of SMAD1, SMAD6, CD34, CXCL1, and APLN in the KD group were signiﬁcantly up-regulated compared with the normal group, whilePITX2 was significantly down-regulated. Conclusion: 102 DEGs in KD serum-induced HCAECs were identified, and six new targets were proposed as potential indicators of KD.

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“…However, two important transcription factors common to development of CEC's and cardiovascular structures are pituitary homeobox 2 (PITX2) and forkhead box C1 (FOXC1). Although CNCC and CEC‐destined NCC's originate from anatomically separate cell fields within the cranial neural crest, work by Silla et al () and Chen et al () has shown that these transcription factors provide key developmental instructions to both. As evidence of the commonalities of heart and eye development, several investigators have reported the coinheritance of corneal/anterior segment dysgenesis syndromes with congenital cardiac defects as reported in studies by Titheradge et al (), Gripp et al (2013), Zhao et al (), Du et al (2014), and Khalil et al ().…”

Section: Introductionmentioning

confidence: 99%

“…The underlying mechanisms responsible for NCC dysfunction in all of these related oculo‐cardiac syndromes are due to genetic mutations in FOXC1 and/or PITX2. Studies by Mears et al (1998), Silla et al (), Chen and Gage (), and Evans and Gage () indicate that correct translation and function of PITX2 and/or FOXC1‐expressed proteins have also been separately demonstrated as essential to normal cardiac or ocular development. Certain mutations of PITX2 and FOXC1are associated with anterior segment dysgenesis without concurrent congenital heart defects as exemplified by the work of Chen et al (), Nishimura et al (), Vieira et al (), Iwao et al (), Reis et al (), Seifi et al (), Mears et al (), Kniestedt et al () Wei et al (), and Sun et al ().…”

Section: Introductionmentioning

confidence: 99%

“…Studies by Mears et al (1998), Silla et al (), Chen and Gage (), and Evans and Gage () indicate that correct translation and function of PITX2 and/or FOXC1‐expressed proteins have also been separately demonstrated as essential to normal cardiac or ocular development. Certain mutations of PITX2 and FOXC1are associated with anterior segment dysgenesis without concurrent congenital heart defects as exemplified by the work of Chen et al (), Nishimura et al (), Vieira et al (), Iwao et al (), Reis et al (), Seifi et al (), Mears et al (), Kniestedt et al () Wei et al (), and Sun et al (). Likewise, during heart development, research by Wei et al (), Sun et al (), and Töpf et al () has shown that PITX2 and FOXC1 mutations are responsible for congenital defects such as transposition of the great vessels, tetralogy of Fallot and ventricular septal defects, in the absence of detectable ocular pathology.…”

Section: Introductionmentioning

confidence: 99%

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Corneal endothelial cell density and cardiovascular mortality

Scherer¹

2018

Clinical Anatomy

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Based on embryological commonalities between eye and heart development, a global, country-specific meta-analysis of normal, adult corneal endothelial cell density (ECD) was performed and correlated against mortality rates secondary to diseases affecting cardiac neural crest cell (CNCC)-derived cardiovascular structures. A country-specific survey of ECD was performed by searching PubMed for studies reporting ECD datasets from normal adults. All eligible datasets were assigned a country of origin. Country-specific weighted mean ECD were calculated based on dataset n. Country-specific disease mortality rates were obtained from the World Health Organization. The correlations between weighted mean ECD and mortality rates secondary to diseases affecting CNCC-derived cardiovascular structures were calculated. As controls, correlations between ECD and noncardiovascular disease mortality were examined. Pearson correlation coefficients (r) corresponding to P-value < 0.05 were considered significant. Three hundred ninety-two datasets (39,762 eyes) from 267 source-studies were assigned to 42 countries. Significant correlations were found between ECD and mortality due to coronary heart disease (r = -0.39, P = 0.011), hypertension (r = -0.33, P = 0.033), and all-cause cardiac disease (r = -0.36, P = 0.019). No significant correlations were found between ECD and mortality secondary to the control conditions: inflammatory heart disease (mesoderm-derived tissues) (r = -0.12, P = 0.45), diabetes (r = -0.13, P = 0.41), lung disease (r = -0.21, P = 0.18), liver disease (r = -0.13, P = 0.41), renal disease (r = -0.10, P = 0.53), lung cancer (r = 0.02, P = 0.90), pancreatic cancer (r = 0.24, P = 0.13), malnutrition (r = -0.07, P = 0.66), or all-cause mortality (r = 0.04, P = 0.81). Negative correlations exist between ECD and mortality due to coronary artery disease and hypertension. On a population-based level, adult ECD is correlated to mortality from certain cardiovascular diseases. Clin. Anat. 31:927-936, 2018. © 2018 Wiley Periodicals, Inc.

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AP-2β Is a Downstream Effector of PITX2 Required to Specify Endothelium and Establish Angiogenic Privilege During Corneal Development

Cited by 31 publications

References 49 publications

Foxc1 and Foxc2 in the Neural Crest Are Required for Ocular Anterior Segment Development

Foxc1 and Foxc2 in the Neural Crest Are Required for Ocular Anterior Segment Development

Expression profile analysis of Differentially Expressed Genes in Human Coronary Artery Endothelial Cells Induced by Serum from Kawasaki Disease: A preliminary study

Corneal endothelial cell density and cardiovascular mortality

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