Regulation of WNT Signaling by VSX2 During Optic Vesicle Patterning in Human Induced Pluripotent Stem Cells

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2016 Jun 15

PMID 27301076

Citations 30

Authors

Elizabeth E Capowski

Lynda S Wright

Kun Liang

M Joseph Phillips

Kyle Wallace

Anna Petelinsek

Anna Hagstrom

Isabel Pinilla

Katarzyna Borys

Jessica Lien

Jee Hong Min

Sunduz Keles

James A Thomson

David M Gamm

Affiliations

Soon will be listed here.

Abstract

Few gene targets of Visual System Homeobox 2 (VSX2) have been identified despite its broad and critical role in the maintenance of neural retina (NR) fate during early retinogenesis. We performed VSX2 ChIP-seq and ChIP-PCR assays on early stage optic vesicle-like structures (OVs) derived from human iPS cells (hiPSCs), which highlighted WNT pathway genes as direct regulatory targets of VSX2. Examination of early NR patterning in hiPSC-OVs from a patient with a functional null mutation in VSX2 revealed mis-expression and upregulation of WNT pathway components and retinal pigmented epithelium (RPE) markers in comparison to control hiPSC-OVs. Furthermore, pharmacological inhibition of WNT signaling rescued the early mutant phenotype, whereas augmentation of WNT signaling in control hiPSC-OVs phenocopied the mutant. These findings reveal an important role for VSX2 as a regulator of WNT signaling and suggest that VSX2 may act to maintain NR identity at the expense of RPE in part by direct repression of WNT pathway constituents. Stem Cells 2016;34:2625-2634.

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References

Meyer J, Howden S, Wallace K, Verhoeven A, Wright L, Capowski E . Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells. 2011; 29(8):1206-18. PMC: 3412675. DOI: 10.1002/stem.674. View

Kharchenko P, Tolstorukov M, Park P . Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nat Biotechnol. 2008; 26(12):1351-9. PMC: 2597701. DOI: 10.1038/nbt.1508. View

Reichman S, Kalathur R, Lambard S, Ait-Ali N, Yang Y, Lardenois A . The homeobox gene CHX10/VSX2 regulates RdCVF promoter activity in the inner retina. Hum Mol Genet. 2009; 19(2):250-61. PMC: 2796890. DOI: 10.1093/hmg/ddp484. View

Momose T, Rohrer H, Yasuda K, Ishihara L, Rapaport D . Multiple functions of fibroblast growth factor-8 (FGF-8) in chick eye development. Mech Dev. 2000; 94(1-2):25-36. DOI: 10.1016/s0925-4773(00)00320-8. View

Van Camp J, Beckers S, Zegers D, Van Hul W . Wnt signaling and the control of human stem cell fate. Stem Cell Rev Rep. 2013; 10(2):207-29. DOI: 10.1007/s12015-013-9486-8. View

Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K . Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012; 10(6):771-785. DOI: 10.1016/j.stem.2012.05.009. View

Lamba D, Karl M, Ware C, Reh T . Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006; 103(34):12769-74. PMC: 1568922. DOI: 10.1073/pnas.0601990103. View

Bar-Yosef U, Abuelaish I, Harel T, Hendler N, Ofir R, Birk O . CHX10 mutations cause non-syndromic microphthalmia/ anophthalmia in Arab and Jewish kindreds. Hum Genet. 2004; 115(4):302-9. DOI: 10.1007/s00439-004-1154-2. View

Dorval K, Bobechko B, Fujieda H, Chen S, Zack D, Bremner R . CHX10 targets a subset of photoreceptor genes. J Biol Chem. 2005; 281(2):744-51. DOI: 10.1074/jbc.M509470200. View

10.

Maruotti J, Sripathi S, Bharti K, Fuller J, Wahlin K, Ranganathan V . Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells. Proc Natl Acad Sci U S A. 2015; 112(35):10950-5. PMC: 4568212. DOI: 10.1073/pnas.1422818112. View

11.

Capowski E, Simonett J, Clark E, Wright L, Howden S, Wallace K . Loss of MITF expression during human embryonic stem cell differentiation disrupts retinal pigment epithelium development and optic vesicle cell proliferation. Hum Mol Genet. 2014; 23(23):6332-44. PMC: 4222367. DOI: 10.1093/hmg/ddu351. View

12.

Nguyen M, Arnheiter H . Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF. Development. 2000; 127(16):3581-91. DOI: 10.1242/dev.127.16.3581. View

13.

Fujimura N, Taketo M, Mori M, Korinek V, Kozmik Z . Spatial and temporal regulation of Wnt/beta-catenin signaling is essential for development of the retinal pigment epithelium. Dev Biol. 2009; 334(1):31-45. DOI: 10.1016/j.ydbio.2009.07.002. View

14.

Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N . Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol. 2008; 26(2):215-24. DOI: 10.1038/nbt1384. View

15.

Hyer J, Mima T, Mikawa T . FGF1 patterns the optic vesicle by directing the placement of the neural retina domain. Development. 1998; 125(5):869-77. DOI: 10.1242/dev.125.5.869. View

16.

Zou C, Levine E . Vsx2 controls eye organogenesis and retinal progenitor identity via homeodomain and non-homeodomain residues required for high affinity DNA binding. PLoS Genet. 2012; 8(9):e1002924. PMC: 3447932. DOI: 10.1371/journal.pgen.1002924. View

17.

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View

18.

Horsford D, Nguyen M, Sellar G, Kothary R, Arnheiter H, McInnes R . Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity. Development. 2004; 132(1):177-87. DOI: 10.1242/dev.01571. View

19.

Munoz-Descalzo S, Hadjantonakis A, Martinez Arias A . Wnt/ß-catenin signalling and the dynamics of fate decisions in early mouse embryos and embryonic stem (ES) cells. Semin Cell Dev Biol. 2015; 47-48:101-9. PMC: 4955857. DOI: 10.1016/j.semcdb.2015.08.011. View

20.

Fuhrmann S . Eye morphogenesis and patterning of the optic vesicle. Curr Top Dev Biol. 2010; 93:61-84. PMC: 2958684. DOI: 10.1016/B978-0-12-385044-7.00003-5. View