FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2905176039> ?p ?o ?g. }

• W2905176039 endingPage "2469" @default.
• W2905176039 startingPage "2460" @default.
• W2905176039 abstract "The corneal endothelium, which originates from the neural crest via the periocular mesenchyme (PM), is crucial for maintaining corneal transparency. The development of corneal endothelial cells (CECs) from the neural crest is accompanied by the expression of several transcription factors, but the contribution of some of these transcriptional regulators to CEC development is incompletely understood. Here, we focused on activating enhancer-binding protein 2 (TFAP2, AP-2), a neural crest–expressed transcription factor. Using semiquantitative/quantitative RT-PCR and reporter gene and biochemical assays, we found that, within the AP-2 family, the TFAP2B gene is the only one expressed in human CECs in vivo and that its expression is strongly localized to the peripheral region of the corneal endothelium. Furthermore, the TFAP2B protein was expressed both in vivo and in cultured CECs. During mouse development, TFAP2B expression began in the PM at embryonic day 11.5 and then in CECs during adulthood. siRNA-mediated knockdown of TFAP2B in CECs decreased the expression of the corneal endothelium–specific proteins type VIII collagen α2 (COL8A2) and zona pellucida glycoprotein 4 (ZP4) and suppressed cell proliferation. Of note, we also found that TFAP2B binds to the promoter of the COL8A2 and ZP4 genes. Furthermore, CECs that highly expressed ZP4 also highly expressed both TFAP2B and COL8A2 and showed high cell proliferation. These findings suggest that TFAP2B transcriptionally regulates CEC-specific genes and therefore may be an important transcriptional regulator of corneal endothelial development and homeostasis. The corneal endothelium, which originates from the neural crest via the periocular mesenchyme (PM), is crucial for maintaining corneal transparency. The development of corneal endothelial cells (CECs) from the neural crest is accompanied by the expression of several transcription factors, but the contribution of some of these transcriptional regulators to CEC development is incompletely understood. Here, we focused on activating enhancer-binding protein 2 (TFAP2, AP-2), a neural crest–expressed transcription factor. Using semiquantitative/quantitative RT-PCR and reporter gene and biochemical assays, we found that, within the AP-2 family, the TFAP2B gene is the only one expressed in human CECs in vivo and that its expression is strongly localized to the peripheral region of the corneal endothelium. Furthermore, the TFAP2B protein was expressed both in vivo and in cultured CECs. During mouse development, TFAP2B expression began in the PM at embryonic day 11.5 and then in CECs during adulthood. siRNA-mediated knockdown of TFAP2B in CECs decreased the expression of the corneal endothelium–specific proteins type VIII collagen α2 (COL8A2) and zona pellucida glycoprotein 4 (ZP4) and suppressed cell proliferation. Of note, we also found that TFAP2B binds to the promoter of the COL8A2 and ZP4 genes. Furthermore, CECs that highly expressed ZP4 also highly expressed both TFAP2B and COL8A2 and showed high cell proliferation. These findings suggest that TFAP2B transcriptionally regulates CEC-specific genes and therefore may be an important transcriptional regulator of corneal endothelial development and homeostasis. The cornea tissue consists of three layers: corneal epithelium, corneal stroma, and corneal endothelium. The corneal endothelium is composed of a monolayer and the Descemet's membrane (1DelMonte D.W. Kim T. Anatomy and physiology of the cornea.J. Cataract Refract. Surg. 2011; 37 (21333881): 588-59810.1016/j.jcrs.2010.12.037Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar). The two major functions of the corneal endothelium are pumping out interstitial fluid from the corneal stroma and serving as a barrier for the stroma to prevent the entry of aqueous humor into the corneal stroma, which eventually prevents the thickening of the cornea (2Bonanno J.A. Identity and regulation of ion transport mechanisms in the corneal endothelium.Prog. Retin. Eye Res. 2003; 22 (12597924): 69-9410.1016/S1350-9462(02)00059-9Crossref PubMed Scopus (165) Google Scholar). Human corneal endothelial cells (CECs) 4The abbreviations used are: CECcorneal endothelial cellCOL8A1COL8A2, type VIII collagen α1, α2FBSfetal bovine serumFOXC1FOXC2, forkhead box C1, C2p75p75 neurotrophin receptorPITX2paired-like homeodomain 2PMperiocular mesenchymeSOX9SOX10, sex-determining region Y (SRY)-box 9, 10TFAP2AP-2, transcription factor activating enhancer-binding protein 2ZO-1zonula occludens 1ZP4zona pellucida glycoprotein 4Eembryonic dayEMSAelectrophoretic mobility shift assayTBSTris-buffered saline. are differentiated from the neural crest via the facial neural crest and periocular mesenchyme (PM) (3Bahn C.F. Falls H.F. Varley G.A. Meyer R.F. Edelhauser H.F. Bourne W.M. Classification of corneal endothelial disorders based on neural crest origin.Ophthalmology. 1984; 91 (6462621): 558-56310.1016/S0161-6420(84)34249-XAbstract Full Text PDF PubMed Scopus (184) Google Scholar). The original neural crest cells express specific differentiation markers, including p75 neurotrophin receptor (p75), SRY-box 9 (SOX9), SOX10, Snail, and Slug. The cranial neural crest, a lineage of the neural crest, gives rise to facial bones, cartilage, peripheral neurons, glia, and parts of the eye (4Santagati F. Rijli F.M. Cranial neural crest and the building of the vertebrate head.Nat. Rev. Neurosci. 2003; 4 (14523380): 806-81810.1038/nrn1221Crossref PubMed Scopus (337) Google Scholar). Around the region of the developing eye, the PM migrates into the space between the surface ectoderm and lens vesicle and then differentiates into the corneal stroma and corneal endothelium. The PM expresses two important transcription factors: paired-like homeodomain 2 (PITX2) and forkhead box C1 (FOXC1) (5Hjalt T.A. Semina E.V. Amendt B.A. Murray J.C. The Pitx2 protein in mouse development.Dev. Dyn. 2000; 218 (10822271): 195-20010.1002/(SICI)1097-0177(200005)218:1<195::AID-DVDY17>3.0.CO;2-CCrossref PubMed Scopus (114) Google Scholar, 6Smith R.S. Zabaleta A. Kume T. Savinova O.V. Kidson S.H. Martin J.E. Nishimura D.Y. Alward W.L. Hogan B.L. John S.W. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development.Hum. Mol. Genet. 2000; 9 (10767326): 1021-103210.1093/hmg/9.7.1021Crossref PubMed Scopus (245) Google Scholar). Mutations in these genes may lead to Axenfeld–Rieger syndrome (7Semina E.V. Reiter R. Leysens N.J. Alward W.L. Small K.W. Datson N.A. Siegel-Bartelt J. Bierke-Nelson D. Bitoun P. Zabel B.U. Carey J.C. Murray J.C. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome.Nat. Genet. 1996; 14 (8944018): 392-39910.1038/ng1296-392Crossref PubMed Scopus (771) Google Scholar, 8Strungaru M.H. Dinu I. Walter M.A. Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations.Invest. Ophthalmol. Vis. Sci. 2007; 48 (17197537): 228-23710.1167/iovs.06-0472Crossref PubMed Scopus (121) Google Scholar), which manifests as abnormalities of the anterior segment of the eye, including the cornea. Previously, we reported that human corneal endothelial progenitor cells retain some properties of both the neural crest and PM, including the expression of p75, SOX9, PITX2, and TFAP2B (9Hara S. Hayashi R. Soma T. Kageyama T. Duncan T. Tsujikawa M. Nishida K. Identification and potential application of human corneal endothelial progenitor cells.Stem Cells Dev. 2014; 23 (24588720): 2190-220110.1089/scd.2013.0387Crossref PubMed Scopus (47) Google Scholar). Most of these are transcriptional factors and thus may regulate some genes specific to CECs, but their detailed contribution to the development of CECs remains unclear. The transcription factor activating enhancer-binding protein 2 (TFAP2, AP-2) family is expressed in the neural crest and consists of five molecules: TFAP2A, TFAP2B, TFAP2C, TFAP2D, and TFAP2E (10Eckert D. Buhl S. Weber S. Jäger R. Schorle H. The AP-2 family of transcription factors.Genome Biol. 2005; 6 (16420676): 24610.1186/gb-2005-6-13-246Crossref PubMed Scopus (319) Google Scholar). The TFAP2 family members have a similar amino acid sequence and play an important role in various developmental stages. TFAP2A, TFAP2B, and TFAP2C are important in neural crest and facial formation. TFAP2D is highly expressed in the heart and retina, and TFAP2E is essential for differentiation and maturation of the olfactory bulb (10Eckert D. Buhl S. Weber S. Jäger R. Schorle H. The AP-2 family of transcription factors.Genome Biol. 2005; 6 (16420676): 24610.1186/gb-2005-6-13-246Crossref PubMed Scopus (319) Google Scholar, 11Lin J.M. Taroc E.Z.M. Frias J.A. Prasad A. Catizone A.N. Sammons M.A. Forni P.E. The transcription factor Tfap2e/AP-2 epsilon plays a pivotal role in maintaining the identity of basal vomeronasal sensory neurons.Dev. Biol. 2018; 441 (29928868): 67-8210.1016/j.ydbio.2018.06.007Crossref PubMed Scopus (13) Google Scholar). The TFAP2 family proteins form a dimer via a helix-span-helix motif and bind to DNA, which is thought to be composed of homodimers or heterodimers (10Eckert D. Buhl S. Weber S. Jäger R. Schorle H. The AP-2 family of transcription factors.Genome Biol. 2005; 6 (16420676): 24610.1186/gb-2005-6-13-246Crossref PubMed Scopus (319) Google Scholar). Joyce et al. (12Joyce N.C. Harris D.L. Markov V. Zhang Z. Saitta B. Potential of human umbilical cord blood mesenchymal stem cells to heal damaged corneal endothelium.Mol. Vis. 2012; 18 (22419848): 547-564PubMed Google Scholar) reported that TFAP2B expression is higher in CECs than in umbilical cord blood mesenchymal stem cells. Recently, we found that TFAP2B is particularly highly expressed in the corneal endothelium (13Yoshihara M. Hara S. Tsujikawa M. Kawasaki S. Hayashizaki Y. Itoh M. Kawaji H. Nishida K. Restricted presence of POU6F2 in human corneal endothelial cells uncovered by extension of the promoter-level expression atlas.EBioMedicine. 2017; 25 (29113774): 175-18610.1016/j.ebiom.2017.10.024Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Several analyses of the human CEC transcriptome using next-generation sequencing have also been reported (13Yoshihara M. Hara S. Tsujikawa M. Kawasaki S. Hayashizaki Y. Itoh M. Kawaji H. Nishida K. Restricted presence of POU6F2 in human corneal endothelial cells uncovered by extension of the promoter-level expression atlas.EBioMedicine. 2017; 25 (29113774): 175-18610.1016/j.ebiom.2017.10.024Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 14Chen Y. Huang K. Nakatsu M.N. Xue Z. Deng S.X. Fan G. Identification of novel molecular markers through transcriptomic analysis in human fetal and adult corneal endothelial cells.Hum. Mol. Genet. 2013; 22 (23257286): 1271-127910.1093/hmg/dds527Crossref PubMed Scopus (44) Google Scholar). In one of these studies, RNA-Seq data showed only TFAP2B to be consistently expressed, and TFAP2A, TFAP2C, and TFAP2D were rarely expressed in adult and fetal CECs. Expression of TFAP2B was higher than the expression of other corneal endothelium–related transcription factors such as ZEB1 (13Yoshihara M. Hara S. Tsujikawa M. Kawasaki S. Hayashizaki Y. Itoh M. Kawaji H. Nishida K. Restricted presence of POU6F2 in human corneal endothelial cells uncovered by extension of the promoter-level expression atlas.EBioMedicine. 2017; 25 (29113774): 175-18610.1016/j.ebiom.2017.10.024Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). corneal endothelial cell COL8A2, type VIII collagen α1, α2 fetal bovine serum FOXC2, forkhead box C1, C2 p75 neurotrophin receptor paired-like homeodomain 2 periocular mesenchyme SOX10, sex-determining region Y (SRY)-box 9, 10 AP-2, transcription factor activating enhancer-binding protein 2 zonula occludens 1 zona pellucida glycoprotein 4 embryonic day electrophoretic mobility shift assay Tris-buffered saline. Regarding their use in regenerative medicine, cultured CECs have limited proliferative ability. Recently, several groups reported that CECs could be generated from multipotent stem cells and somatic stem cells (15Ju C. Zhang K. Wu X. Derivation of corneal endothelial cell-like cells from rat neural crest cells in vitro.PLoS One. 2012; 7 (22860120): e4237810.1371/journal.pone.0042378Crossref PubMed Scopus (37) Google Scholar16Hatou S. Yoshida S. Higa K. Miyashita H. Inagaki E. Okano H. Tsubota K. Shimmura S. Functional corneal endothelium derived from corneal stroma stem cells of neural crest origin by retinoic acid and Wnt/β-catenin signaling.Stem Cells Dev. 2013; 22 (22974347): 828-83910.1089/scd.2012.0286Crossref PubMed Scopus (88) Google Scholar, 17Zhang K. Pang K. Wu X. Isolation and transplantation of corneal endothelial cell-like cells derived from in-vitro-differentiated human embryonic stem cells.Stem Cells Dev. 2014; 23 (24499373): 1340-135410.1089/scd.2013.0510Crossref PubMed Scopus (77) Google Scholar, 18McCabe K.L. Kunzevitzky N.J. Chiswell B.P. Xia X. Goldberg J.L. Lanza R. Efficient generation of human embryonic stem cell-derived corneal endothelial cells by directed differentiation.PLoS One. 2015; 10 (26689688): e014526610.1371/journal.pone.0145266Crossref PubMed Scopus (58) Google Scholar19Chen P. Chen J.Z. Shao C.Y. Li C.Y. Zhang Y.D. Lu W.J. Fu Y. Gu P. Fan X. Treatment with retinoic acid and lens epithelial cell-conditioned medium directed the differentiation of pluripotent stem cells towards corneal endothelial cell-like cells.Exp. Ther. Med. 2015; 9 (25574197): 351-36010.3892/etm.2014.2103Crossref PubMed Scopus (41) Google Scholar), but only a few studies have demonstrated the purity of CECs. In our previous study, we found that the ZP4 molecule was a novel CEC-specific marker and was expressed in both in vivo and in vitro cultured CECs (20Yoshihara M. Ohmiya H. Hara S. Kawasaki S. FANTOM consortium Hayashizaki Y. Itoh M. Kawaji H. Tsujikawa M. Nishida K. Discovery of molecular markers to discriminate corneal endothelial cells in the human body.PLoS One. 2015; 10 (25807145): e011758110.1371/journal.pone.0117581PubMed Google Scholar). However, to the best of our knowledge, there are few reports on specific transcription factors regulating CEC-specific functions, which are presumably controlled by several CEC-specific genes. The transcriptional regulation mechanism of TFAP2B in other tissues is not clear, and it is important to explore how it relates to the physiological function of the corneal endothelium. In this study, we examined the transcriptional regulation mechanism of the TFAP2B gene, which may lead to the elucidation of differentiation mechanisms important for the study of cell-based therapy in corneal endothelial regeneration. The expression pattern of the AP-2 family in the human corneal endothelium was confirmed by RT-PCR. TFAP2B mRNA was detected, whereas the mRNAs of other family members, TFAP2A, TFAP2C, TFAP2D, and TFAP2E, were not detected (Fig. 1A). TFAP2B protein was expressed in human CECs in vivo (Fig. 1B) with varying expression levels; the expression level in the peripheral region was 2.5-fold greater than that in the central region (Fig. 1C), and cells highly expressing TFAP2B were localized in the vicinity of the transition zone. Additionally, the TFAP2B protein was also expressed in in vitro cultured CECs (Fig. 1D). It has been reported that TFAP2B is important for mouse corneal endothelial development, particularly at E11.5 (when the PM migrates between the lens and corneal epithelium) and at E15.5 (when the corneal endothelium forms a single cell layer) (21Swamynathan S.K. Ocular surface development and gene expression.J. Ophthalmol. 2013; 2013 (23533700): 10394710.1155/2013/103947Crossref PubMed Scopus (40) Google Scholar). To investigate the distribution of TFAP2B during development, we performed immunofluorescence studies using both mouse embryos and adult mice. At E11.5, TFAP2B-expressing cells were localized in the PM (Fig. 2, A–D), whereas at E15.5 (Fig. 2, E–H) and adulthood (Fig. 2, I–L), TFAP2B was expressed in mouse CECs. These results suggested that TFAP2B protein was expressed in the PM and during subsequent steps and that it might be involved in gene regulation during CEC differentiation. TFAP2B was expressed in mouse CECs throughout all developing stages, from E11 to adulthood, possibly indicating that TFAP2B protein controls the expression of key molecules in CEC development and homeostasis. Then, to test whether genes are regulated by TFAP2B in cultured human CECs, we first analyzed its contribution using siRNA-mediated knockdown. The expression patterns of the neural crest marker SOX9; periocular mesenchyme markers PITX2, FOXC1, and FOXC2; and CEC markers ZO-1, Na+/K+-ATPase, COL8A1, COL8A2, and ZP4 were investigated using qRT-PCR in siRNA-treated CECs. Interestingly, the expression levels of COL8A2 and ZP4 mRNA in TFAP2B siRNA–transfected cells were significantly lower than those in the control siRNA–transfected cells (Fig. 3A). Furthermore, we validated their protein expression levels by Western blotting (Fig. 3B). COL8A2, which is the main component of the Descemet’s membrane synthesized from CECs, and ZP4, which is a plasma membranous protein, were selectively expressed in vivo in the corneal endothelium (Fig. 3C). In a whole-mount immunofluorescence study of the human corneal endothelium tissue, we found that ZP4 protein was strongly expressed in cells highly expressing TFAP2B (Fig. 3D) compared with those weakly expressing TFAP2B. In the cell proliferation assay, the proliferative capacity of TFAP2B siRNA–treated CECs also decreased compared with that of control siRNA–treated CECs (Fig. 3E). These data suggest that TFAP2B regulates the corneal endothelial cell–specific markers COL8A2 and ZP4 and promotes cell proliferation. Next, we determined the effect of TFAP2B on transcriptional activity in the COL8A2 and ZP4 promoters. A luciferase reporter assay was performed to identify the TFAP2B-binding motif in cultured CECs. In previous reports, a sequence consisting of nine nucleotides, 5′-S(G/C)CCTSR(A/G)GGS-3′, was reported to be a common binding sequence of the AP-2 family genes (22Woodfield G.W. Chen Y. Bair T.B. Domann F.E. Weigel R.J. Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells.Genes Chromosomes Cancer. 2010; 49 (20629094): 948-96210.1002/gcc.20807Crossref PubMed Scopus (67) Google Scholar, 23Zhao F. Weismann C.G. Satoda M. Pierpont M.E. Sweeney E. Thompson E.M. Gelb B.D. Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation.Am. J. Hum. Genet. 2001; 69 (11505339): 695-70310.1086/323410Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). This AP-2–binding consensus sequence was found in the upstream region of the human COL8A2 and ZP4 promoters, both at approximately −3.0 kbp from their respective transcriptional start sites (Fig. 4, A and E). First, we performed EMSA to determine whether TFAP2B binds to the sequences of COL8A2 and ZP4. The results showed that the shifted bands were located in the WT sequences, but the artificially introduced mutation sequences did not bind to TFAP2B proteins (Fig. 4, B and F). The luciferase activity was found to be markedly high in the promoter region–containing vectors compared with that in the basic control vector (Fig. 4, C and G). The artificially introduced mutation within the TFAP2B candidate binding sites in the COL8A2 and ZP4 promoter regions significantly decreased luciferase activity in TFAP2B-overexpressing 293T cells (Fig. 4, B and E). For each gene, we also performed ChIP-PCR with anti-TFAP2B antibody in CECs. The assay confirmed the binding of TFAP2B proteins to the candidate binding site within the promoters of the COL8A2 and ZP4 genes in the primary CECs (Fig. 4, D and H). These data indicate that TFAP2B protein directly regulates the transcriptional activities of the COL8A2 and ZP4 genes in CECs. Because ZP4 has been reported as one of the cell-surface proteins (24da Cunha J.P. Galante P.A. de Souza J.E. de Souza R.F. Carvalho P.M. Ohara D.T. Moura R.P. Oba-Shinja S.M. Marie S.K. Silva Jr., W.A. Perez R.O. Stransky B. Pieprzyk M. Moore J. Caballero O. et al.Bioinformatics construction of the human cell surfaceome.Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (19805368): 16752-1675710.1073/pnas.0907939106Crossref PubMed Scopus (96) Google Scholar), we isolated ZP4-expressing CECs using an anti-ZP4 antibody by FACS. To confirm the relationship between the expression of TFAP2B and ZP4, we performed purification experiments with cultured human CECs using an anti-ZP4 antibody. Among the cultured CECs, 14.4% of the cells were positively stained by ZP4 (Fig. 5A). qRT-PCR analysis demonstrated that the ZP4-expressing cells had significantly higher expression levels of TFAP2B and COL8A2, but those of COL8A1 were not significantly different (Fig. 5B). When ZP4-positive and ZP4-negative cells were respectively cultured, it was found that TFAP2B expression was high in ZP4-positive cells by immunofluorescence (Fig. 5C). Furthermore, ZP4-positive cells had a higher proliferative ability than ZP4-negative cells (Fig. 5, D and E). These data suggest that ZP4-expressing CECs may have a high proliferative potential. We previously identified TFAP2B as one of the corneal endothelium–specific transcription factors (13Yoshihara M. Hara S. Tsujikawa M. Kawasaki S. Hayashizaki Y. Itoh M. Kawaji H. Nishida K. Restricted presence of POU6F2 in human corneal endothelial cells uncovered by extension of the promoter-level expression atlas.EBioMedicine. 2017; 25 (29113774): 175-18610.1016/j.ebiom.2017.10.024Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). However, it was not clear which genes were transcriptionally controlled by TFAP2B in CECs. Here, we demonstrate that the expression levels of functional markers such as ZO-1 and Na+/K+-ATPase and periocular mesenchymal markers such as PITX2 and FOXC1 were not affected by the knockdown of TFAP2B in CECs. It is possible that TFAP2B may play a different role between corneal endothelium–specific genes such as COL8A2 and ZP4 and functional markers that are not specific to CECs such as ZO-1 and Na+/K+-ATPase. However, it was previously reported that TFAP2B is required for the expression of ZO-1 in the corneal endothelium and is responsible for the barrier function during corneal development (25Chen L. Martino V. Dombkowski A. Williams T. West-Mays J. Gage P.J. AP-2β is a downstream effector of PITX2 required to specify endothelium and establish angiogenic privilege during corneal development.Invest. Ophthalmol Vis. Sci. 2016; 57 (26968737): 1072-108110.1167/iovs.15-18103Crossref PubMed Scopus (22) Google Scholar). Systemically, the expression of TFAP2B has been found in various tissues such as the skin, spinal cord, renal tubular epithelia, facial mesenchyme, and cornea (26Nelms B.L. Labosky P.A. Transcriptional Control of Neural Crest Development. Morgan and Claypool Life Sciences, San Rafael, CA2010Crossref Google Scholar). Mutation of the TFAP2B gene is known to cause Char syndrome, an autosomal dominant disease characterized by facial dysmorphism (27Satoda M. Zhao F. Diaz G.A. Burn J. Goodship J. Davidson H.R. Pierpont M.E. Gelb B.D. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.Nat. Genet. 2000; 25 (10802654): 42-4610.1038/75578Crossref PubMed Scopus (222) Google Scholar). Additionally, TFAP2B-deficient mice die in the postnatal period due to polycystic kidney disease (28Moser M. Rüschoff J. Buettner R. Comparative analysis of AP-2α and AP-2β gene expression during murine embryogenesis.Dev. Dyn. 1997; 208 (8989526): 115-12410.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2–5Crossref PubMed Scopus (140) Google Scholar). Recently, in the eye, the TFAP2B gene was suggested to be an early-onset glaucoma-causing gene in an analysis of periocular mesenchyme–specific TFAP2B knockout mice (29Martino V.B. Sabljic T. Deschamps P. Green R.M. Akula M. Peacock E. Ball A. Williams T. West-Mays J.A. Conditional deletion of AP-2β in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma.Dis. Model. Mech. 2016; 9 (27483349): 849-86110.1242/dmm.025262Crossref PubMed Scopus (26) Google Scholar). However, disorders associated with TFAP2B in CECs have not been reported. COL8A2 is one of the major components of the Descemet's membrane along with COL8A1 and is generated from CECs (30Muragaki Y. Mattei M.G. Yamaguchi N. Olsen B.R. Ninomiya Y. The complete primary structure of the human α1 (VIII) chain and assignment of its gene (COL8A1) to chromosome 3.Eur. J. Biochem. 1991; 197 (2029894): 615-62210.1111/j.1432-1033.1991.tb15951.xCrossref PubMed Scopus (42) Google Scholar), and mutations of the COL8A2 gene were reported to cause Fuchs endothelial corneal dystrophy (31Gottsch J.D. Sundin O.H. Liu S.H. Jun A.S. Broman K.W. Stark W.J. Vito E.C. Narang A.K. Thompson J.M. Magovern M. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy.Invest. Ophthalmol. Vis. Sci. 2005; 46 (15914606): 1934-193910.1167/iovs.04-0937Crossref PubMed Scopus (160) Google Scholar, 32Mok J.W. Kim H.S. Joo C.K. Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients.Eye. 2009; 23 (18464802): 895-90310.1038/eye.2008.116Crossref PubMed Scopus (60) Google Scholar). Moreover, the COL8A1/COL8A2 double-null mouse phenotype was found to be associated with anterior segment abnormality in the cornea (33Hopfer U. Fukai N. Hopfer H. Wolf G. Joyce N. Li E. Olsen B.R. Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye.FASEB J. 2005; 19 (16051690): 1232-124410.1096/fj.04-3019comCrossref PubMed Scopus (93) Google Scholar). We speculate that the relationship between TFAP2B and COL8A2 may be crucial in the developmental stage in CECs. We also identified ZP4 as a target gene of TFAP2B wherein TFAP2B binds to the ZP4 promoter region and directly induces the expression of the ZP4 protein. Furthermore, we found that ZP4 is a specific surface marker of human CECs (20Yoshihara M. Ohmiya H. Hara S. Kawasaki S. FANTOM consortium Hayashizaki Y. Itoh M. Kawaji H. Tsujikawa M. Nishida K. Discovery of molecular markers to discriminate corneal endothelial cells in the human body.PLoS One. 2015; 10 (25807145): e011758110.1371/journal.pone.0117581PubMed Google Scholar). Several corneal endothelial markers have previously been isolated such as sodium bicarbonate transporter–like protein 11, COL8A2, cysteine- and tyrosine-rich protein 1, glypican-4, cluster of differentiation 200 (CD200), and ZP4 (34Chng Z. Peh G.S. Herath W.B. Cheng T.Y. Ang H.P. Toh K.P. Robson P. Mehta J.S. Colman A. High throughput gene expression analysis identifies reliable expression markers of human corneal endothelial cells.PLoS One. 2013; 8 (23844023): e6754610.1371/journal.pone.0067546Crossref PubMed Scopus (46) Google Scholar, 35Cheong Y.K. Ngoh Z.X. Peh G.S. Ang H.P. Seah X.Y. Chng Z. Colman A. Mehta J.S. Sun W. Identification of cell surface markers glypican-4 and CD200 that differentiate human corneal endothelium from stromal fibroblasts.Invest. Ophthalmol. Vis. Sci. 2013; 54 (23744997): 4538-454710.1167/iovs.13-11754Crossref PubMed Scopus (47) Google Scholar). We previously showed that ZP4 was expressed in human CECs, oocytes, and other eye tissues but had little to no expression elsewhere in the body (20Yoshihara M. Ohmiya H. Hara S. Kawasaki S. FANTOM consortium Hayashizaki Y. Itoh M. Kawaji H. Tsujikawa M. Nishida K. Discovery of molecular markers to discriminate corneal endothelial cells in the human body.PLoS One. 2015; 10 (25807145): e011758110.1371/journal.pone.0117581PubMed Google Scholar). Although the specific function of ZP4 in CECs remains unclear, our data indicate that it is expressed in CECs with high proliferative capacity. We were able to isolate ZP4-expressing cells via FACS and found that ZP4 protein–expressing cells correlated with the increased expression of TFAP2B and COL8A2. Known corneal endothelial stem/progenitor markers such as p75, Ki67, leucine-rich repeat–containing G protein–coupled receptor 5, nestin, and telomerase are all localized in the peripheral region of the corneal endothelium (9Hara S. Hayashi R. Soma T. Kageyama T. Duncan T. Tsujikawa M. Nishida K. Identification and potential application of human corneal endothelial progenitor cells.Stem Cells Dev. 2014; 23 (24588720): 2190-220110.1089/scd.2013.0387Crossref PubMed Scopus (47) Google Scholar, 36Yokoo S. Yamagami S. Yanagi Y. Uchida S. Mimura T. Usui T. Amano S. Human corneal endothelial cell precursors isolated by sphere-forming assay.Invest. Ophthalmol. Vis. Sci. 2005; 46 (15851561): 1626-163110.1167/iovs.04-1263Crossref PubMed Scopus (126) Google Scholar, 37He Z. Campolmi N. Gain P. Ha Thi B.M. Dumollard J.M. Duband S. Peoc'h M. Piselli S. Garraud O. Thuret G. Revisited microanatomy of the corneal endothelial periphery: new evidence for continuous centripetal migration of endothelial cells in humans.Stem Cells. 2012; 30 (22949402): 2523-253410.1002/stem.1212Crossref PubMed Scopus (101) Google Scholar38Hirata-Tominaga K. Nakamura T. Okumura N. Kawasaki S. Kay E.P. Barrandon Y. Koizumi N. Kinoshita S. Corneal endothelial cell fate is maintained by LGR5 through the regulation of Hedgehog and Wnt Pathway.Stem Cells. 2013; 31 (23553870): 1396-140710.1002/stem.1390Crossref PubMed Scopus (65) Google Scholar). Of these, we previously reported that p75 was expressed in human corneal endothelial progenitor cells as a neural crest stem cell marker (9Hara S. Hayashi R. Soma T. Kageyama T. Duncan T. Tsujikawa M. Nishida K. Identification and potential app" @default.
• W2905176039 created "2018-12-22" @default.
• W2905176039 creator A5007831725 @default.
• W2905176039 creator A5008948032 @default.
• W2905176039 creator A5033571681 @default.
• W2905176039 creator A5057804128 @default.
• W2905176039 creator A5063101661 @default.
• W2905176039 creator A5077941466 @default.
• W2905176039 creator A5087193515 @default.
• W2905176039 date "2019-02-01" @default.
• W2905176039 modified "2023-10-18" @default.
• W2905176039 title "Transcription factor TFAP2B up-regulates human corneal endothelial cell–specific genes during corneal development and maintenance" @default.
• W2905176039 cites W1854656747 @default.
• W2905176039 cites W1860599747 @default.
• W2905176039 cites W1902708463 @default.
• W2905176039 cites W1976845238 @default.
• W2905176039 cites W1978199155 @default.
• W2905176039 cites W1979588065 @default.
• W2905176039 cites W1993219323 @default.
• W2905176039 cites W1993299801 @default.
• W2905176039 cites W1998591853 @default.
• W2905176039 cites W1998788328 @default.
• W2905176039 cites W2012535202 @default.
• W2905176039 cites W2014829486 @default.
• W2905176039 cites W2015593839 @default.
• W2905176039 cites W2029506276 @default.
• W2905176039 cites W2034607546 @default.
• W2905176039 cites W2041709838 @default.
• W2905176039 cites W2043467634 @default.
• W2905176039 cites W2046696024 @default.
• W2905176039 cites W2057625985 @default.
• W2905176039 cites W2058849934 @default.
• W2905176039 cites W2062598900 @default.
• W2905176039 cites W2067977003 @default.
• W2905176039 cites W2069087563 @default.
• W2905176039 cites W2069628319 @default.
• W2905176039 cites W2076221823 @default.
• W2905176039 cites W2078325889 @default.
• W2905176039 cites W2082222631 @default.
• W2905176039 cites W2083232552 @default.
• W2905176039 cites W2096418253 @default.
• W2905176039 cites W2102079388 @default.
• W2905176039 cites W2102112915 @default.
• W2905176039 cites W2102442664 @default.
• W2905176039 cites W2127805347 @default.
• W2905176039 cites W2167332680 @default.
• W2905176039 cites W2233687295 @default.
• W2905176039 cites W2341596172 @default.
• W2905176039 cites W2464789860 @default.
• W2905176039 cites W2766402115 @default.
• W2905176039 cites W2766456821 @default.
• W2905176039 cites W2952152246 @default.
• W2905176039 doi "https://doi.org/10.1074/jbc.ra118.005527" @default.
• W2905176039 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6378988" @default.
• W2905176039 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30552118" @default.
• W2905176039 hasPublicationYear "2019" @default.
• W2905176039 type Work @default.
• W2905176039 sameAs 2905176039 @default.
• W2905176039 citedByCount "9" @default.
• W2905176039 countsByYear W29051760392019 @default.
• W2905176039 countsByYear W29051760392020 @default.
• W2905176039 countsByYear W29051760392021 @default.
• W2905176039 crossrefType "journal-article" @default.
• W2905176039 hasAuthorship W2905176039A5007831725 @default.
• W2905176039 hasAuthorship W2905176039A5008948032 @default.
• W2905176039 hasAuthorship W2905176039A5033571681 @default.
• W2905176039 hasAuthorship W2905176039A5057804128 @default.
• W2905176039 hasAuthorship W2905176039A5063101661 @default.
• W2905176039 hasAuthorship W2905176039A5077941466 @default.
• W2905176039 hasAuthorship W2905176039A5087193515 @default.
• W2905176039 hasBestOaLocation W29051760391 @default.
• W2905176039 hasConcept C104317684 @default.
• W2905176039 hasConcept C2775901793 @default.
• W2905176039 hasConcept C2776992346 @default.
• W2905176039 hasConcept C54355233 @default.
• W2905176039 hasConcept C86339819 @default.
• W2905176039 hasConcept C86803240 @default.
• W2905176039 hasConcept C95444343 @default.
• W2905176039 hasConceptScore W2905176039C104317684 @default.
• W2905176039 hasConceptScore W2905176039C2775901793 @default.
• W2905176039 hasConceptScore W2905176039C2776992346 @default.
• W2905176039 hasConceptScore W2905176039C54355233 @default.
• W2905176039 hasConceptScore W2905176039C86339819 @default.
• W2905176039 hasConceptScore W2905176039C86803240 @default.
• W2905176039 hasConceptScore W2905176039C95444343 @default.
• W2905176039 hasFunder F4320334764 @default.
• W2905176039 hasIssue "7" @default.
• W2905176039 hasLocation W29051760391 @default.
• W2905176039 hasLocation W29051760392 @default.
• W2905176039 hasLocation W29051760393 @default.
• W2905176039 hasOpenAccess W2905176039 @default.
• W2905176039 hasPrimaryLocation W29051760391 @default.
• W2905176039 hasRelatedWork W1969676666 @default.
• W2905176039 hasRelatedWork W2009966535 @default.
• W2905176039 hasRelatedWork W2019988726 @default.
• W2905176039 hasRelatedWork W2051461989 @default.
• W2905176039 hasRelatedWork W2088063203 @default.
• W2905176039 hasRelatedWork W2097265502 @default.

• next