The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea

Gage, Philip J.; Chen, Kuang; Zacharias, Amanda L.

doi:10.1002/dvdy.24165

Cited by 40 publications

(44 citation statements)

References 33 publications

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“…11 These observations would be consistent with the results from previous reports that suggest Wnt signaling plays an important role in ocular surface homeostasis by regulating limbal stem cell proliferation 57 and corneal epithelium identity. 50 In conclusion, our findings identify Foxc1 and Foxc2 as key regulators of canonical Wnt signaling in the development and maintenance of the ocular surface including the cornea.…”

Section: Discussionsupporting

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: Discussionsupporting

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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“…HAND2 and SIX2 genes, which code for transcription factors, have also been found hypermethylated in several cancer types (Rauch et al 2006;Tong et al 2010;Jones et al 2013). In contrast, the genes that are hypomethylated during MSC aging-TBX15, PITX2, and HOXA11-code for transcription factors involved in several differentiation and developmental processes (Singh et al 2005;Gross et al 2012;Gage et al 2014).…”

Section: Discussionmentioning

confidence: 99%

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

et al. 2014

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In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.

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“…40,58 Examples of RA-target genes in the cornea include transcription factors that are either upregulated (PITX2, DKK2, PAX6, TFAP2β) or downregulated (SOX9, MSX1, OTX2, LMO2) ( Figure 3A,E, and Supplementary Table S4). Pitx2, Foxc1, Pax6 play important roles during mouse corneal development, [59][60][61] and they are among the ASD genes linked to dysgenesis of the human cornea. 8…”

Section: Ra Signaling Pathwaymentioning

confidence: 99%

Transcriptomic analysis of differential gene expression during chick periocular neural crest differentiation into corneal cells

Lwigale

2019

Developmental Dynamics

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Background: Multipotent neural crest cells (NCC) contribute to the corneal endothelium and keratocytes during ocular development, but the molecular mechanisms that underlie this process remain poorly understood. We performed RNA-Seq analysis on periocular neural crest (pNC), corneal endothelium, and keratocytes and validated expression of candidate genes by in situ hybridization. Results: RNA-Seq profiling revealed enrichment of genes between pNC and neural crest-derived corneal cells, which correspond to pathways involved in focal adhesion, ECM-receptor interaction, cell adhesion, melanogenesis, and MAPK signaling. Comparisons of candidate NCC genes to ocular gene expression revealed that majority of the NCC genes are expressed in the pNC, but they are either differentially expressed or maintained during corneal development. Several genes involved in RA, TGFβ, and Wnt signaling pathways and their modulators are also differentially expressed. We identified differentially expressed transcription factors as potential downstream candidates that may instruct expression of genes involved in establishing corneal endothelium and keratocyte identities. Conclusion: Combined, our data reveal novel changes in gene expression profiles as pNC differentiate into highly specialized corneal endothelial cells and keratocytes. These data serve as platform for further analyses of the molecular networks involved in NCC differentiation into corneal cells, and provide insights into genes involved in corneal dysgenesis and adult diseases.

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The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea

Cited by 40 publications

References 33 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

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

Transcriptomic analysis of differential gene expression during chick periocular neural crest differentiation into corneal cells

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