TY - JOUR
T1 - Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation
AU - Diacou, Raven
AU - Zhao, Yilin
AU - Zheng, Deyou
AU - Cvekl, Ales
AU - Liu, Wei
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/11/27
Y1 - 2018/11/27
N2 - Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either Six3 nulls or Six6 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/β-catenin signaling by either Wnt-3a or a GS3Kβ inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/β-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors. Gene regulation of multipotent retinal progenitor cells is partially understood. Through genetic, molecular, and transcriptomic characterization of Six3 and Six6 compound null retinas in mice, Diacou et al. demonstrate that Six3 and Six6 jointly suppress Wnt/β-catenin signaling but promote the expression of retinogenic factors to maintain multipotent retinal progenitor cells.
AB - Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either Six3 nulls or Six6 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/β-catenin signaling by either Wnt-3a or a GS3Kβ inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/β-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors. Gene regulation of multipotent retinal progenitor cells is partially understood. Through genetic, molecular, and transcriptomic characterization of Six3 and Six6 compound null retinas in mice, Diacou et al. demonstrate that Six3 and Six6 jointly suppress Wnt/β-catenin signaling but promote the expression of retinogenic factors to maintain multipotent retinal progenitor cells.
KW - Six3
KW - Six6
KW - Wnt/β-catenin signaling
KW - cell differentiation
KW - cell fate specification
KW - ciliary margin progenitor
KW - multipotent neuroretinal progenitor
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U2 - 10.1016/j.celrep.2018.10.106
DO - 10.1016/j.celrep.2018.10.106
M3 - Article
C2 - 30485816
AN - SCOPUS:85056716944
SN - 2211-1247
VL - 25
SP - 2510-2523.e4
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -