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Wei Liu, Xue Li, Ales Cvekl, Guillermo Oliver; Retinal Proliferation And Differentiation Require Functional Cooperation Between Six3 And Six6 In Mouse. Invest. Ophthalmol. Vis. Sci. 2011;52(14):26.
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© ARVO (1962-2015); The Authors (2016-present)
Six3 and Six6 (also known as Optx2) are structurally similar homeodomain-containing transcription factors implicated in mammalian retinal development. We have recently shown that Six3-mediated suppression of Wnt8b in the anterior neural plate is required for the specification of retinal progenitors. However, conditional inactivation of Six3 at later developmental stages (E10.5) did not show any obvious retinal abnormalities. Thus, we hypothesized that Six6 could functionally compensate the loss of Six3 during subsequent stages of mouse retinogenesis.
To bypass the early forebrain truncation phenotype described in Six3 null embryos, conditional Six3 mutant mice crossed with available Six6 mutant mice to generate Six3;Six6 double null embryo. CAGG-CreER line was used to conditionally delete floxed Six3 with administration of Tamoxifen via intraperitoneal injection at E9.5 and E10.5. Standard protocols for immunohistochemistry, in situ hybridizations and TUNEL were used.
Inactivation of Six6 or Six3 alone did not cause any major defect in retinal proliferation and differentiation in NMRI background. In contrast, the retina of Six3 and Six6 double mutant embryos exhibited drastically reduced proliferation and substantially increased apoptosis. In addition, the expression of the bHLH transcription factors Neurog2 and Math5, and the ganglion cell markers Brn3n and Islet1 was drastically reduced. This phenotype is similar to the one described in Sox2 mutant embryos. Finally, we found that the expression of Sox2 and its downstream target Notch1 were severely reduced or absent in Six3;Six6 compound null embryos. Expression of other HD-containing genes, Pax6 and Rax, was not affected.
Our data demonstrate that mouse retinal cell proliferation, differentiation and survival require both Six3 and Six6 genes. We propose that cooperative function between Six3 and Six6 controls the Sox2/Notch1 signaling pathway.
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