Purchase this article with an account.
Wei Liu, Raven Diacou, Yilin Zhao, Deyou Zheng, Ales Cvekl; Molecular targets of homeodomain transcription factor Six3 and Six6 in murine retinal differentiation. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6027.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Homeodomain transcription factors Six3 and Six6 are crucial for retinal differentiation. We aim to identify molecular targets of Six3 and Six6 in the regulation of multipotent retinal progenitors.
Methods: 1) phenotypic analysis of Six3 and Six6 compound mutant retinas; 2) transcriptomic profiling; 3) ChIP-seq.
Conditional Six3 deletion driven by α-Cre in combination with Six6 deletion caused drastic retinal phenotypes that were not found in either conditional Six3 null or Six6 null retinas. At the far periphery of Six3 and Six6 compound null retinas, ciliary margin markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically up-regulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. The ectopic upregulation of Otx1, Wnt3a, and Fzd1 was an early response to conditional Six3 deletion. At the mid periphery of the compound null retinas, multi-lineage differentiation was defective. RNA-seq profiling revealed that 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 ciliary margin progenitors at the cost of neuroretinal identity at the periphery of eyecups. Six3 occupancy in the mouse genome is being determined using ChIP-seq.
Six3 and Six6 together directly or indirectly suppress Wnt/β-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors. Otx1, Wnt3a, and Fzd1 are among the candidate targets of Six3 and Six6 in the regulation of multipotent retinal progenitors.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only