000205554 001__ 205554
000205554 005__ 20190522142440.0
000205554 0247_ $$2doi$$a10.1093/hmg/ddu351
000205554 022__ $$a0964-6906
000205554 02470 $$2ISI$$a000346777400016
000205554 037__ $$aARTICLE
000205554 245__ $$aLoss of MITF expression during human embryonic stem cell differentiation disrupts retinal pigment epithelium development and optic vesicle cell proliferation
000205554 260__ $$c2014$$bOxford University Press$$aOxford
000205554 269__ $$a2014
000205554 300__ $$a13
000205554 336__ $$aJournal Articles
000205554 500__ $$aNational Licences
000205554 520__ $$aMicrophthalmia-associated transcription factor (MITF) is a master regulator of pigmented cell survival and differentiation with direct transcriptional links to cell cycle, apoptosis and pigmentation. In mouse, Mitf is expressed early and uniformly in optic vesicle (OV) cells as they evaginate from the developing neural tube, and null Mitf mutations result in microphthalmia and pigmentation defects. However, homozygous mutations in MITF have not been identified in humans; therefore, little is known about its role in human retinogenesis. We used a human embryonic stem cell (hESC) model that recapitulates numerous aspects of retinal development, including OV specification and formation of retinal pigment epithelium (RPE) and neural retina progenitor cells (NRPCs), to investigate the earliest roles of MITF. During hESC differentiation toward a retinal lineage, a subset of MITF isoforms was expressed in a sequence and tissue distribution similar to that observed in mice. In addition, we found that promoters for the MITF-A, -D and -H isoforms were directly targeted by Visual Systems Homeobox 2 (VSX2), a transcription factor involved in patterning the OV toward a NRPC fate. We then manipulated MITF RNA and protein levels at early developmental stages and observed decreased expression of eye field transcription factors, reduced early OV cell proliferation and disrupted RPE maturation. This work provides a foundation for investigating MITF and other highly complex, multi-purposed transcription factors in a dynamic human developmental model system.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aCapowski, Elizabeth E.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aSimonett, Joseph M.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aClark, Eric M.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aWright, Lynda S.
000205554 700__ $$uMorgridge Inst Res, Madison, WI 53715 USA$$aHowden, Sara E.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aWallace, Kyle A.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aPetelinsek, Anna M.
000205554 700__ $$uUniv Hosp Lozano Blesa, Dept Ophthalmol, Zaragoza 50009, Spain$$aPinilla, Isabel
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aPhillips, M. Joseph
000205554 700__ $$uIndiana Univ Purdue Univ, Dept Biol, Indianapolis, IN 46202 USA$$aMeyer, Jason S.
000205554 700__ $$uEcole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland$$aSchneider, Bernard L.
000205554 700__ $$uMorgridge Inst Res, Madison, WI 53715 USA$$aThomson, James A.
000205554 700__ $$uUniv Wisconsin, Waisman Ctr, Madison, WI 53705 USA$$aGamm, David M.
000205554 773__ $$j23$$tHuman Molecular Genetics$$k23$$q6332-6344
000205554 8564_ $$uhttps://infoscience.epfl.ch/record/205554/files/ddu351.pdf$$zPUBLISHER'S VERSION$$s1206447
000205554 909C0 $$xU10454$$0252449$$pBMI
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000205554 937__ $$aEPFL-ARTICLE-205554
000205554 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000205554 980__ $$aARTICLE