Liu Wei, Lagutin Oleg V, Mende Michael, Streit Andrea, Oliver Guillermo
Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
EMBO J. 2006 Nov 15;25(22):5383-95. doi: 10.1038/sj.emboj.7601398. Epub 2006 Oct 26.
The homeobox gene Six3 regulates forebrain development. Here we show that Six3 is also crucial for lens formation. Conditional deletion of mouse Six3 in the presumptive lens ectoderm (PLE) disrupted lens formation. In the most severe cases, lens induction and specification were defective, and the lens placode and lens were absent. In Six3-mutant embryos, Pax6 was downregulated, and Sox2 was absent in the lens preplacodal ectoderm. Using ChIP, electrophoretic mobility shift assay, and luciferase reporter assays, we determined that Six3 activates Pax6 and Sox2 expression. Misexpression of mouse Six3 into chick embryos promoted the ectopic expansion of the ectodermal Pax6 expression domain. Our results position Six3 at the top of the regulatory pathway leading to lens formation. We conclude that Six3 directly activates Pax6 and probably also Sox2 in the PLE and regulates cell autonomously the earliest stages of mammalian lens induction.
同源框基因Six3调节前脑发育。在此我们表明，Six3对晶状体形成也至关重要。在假定的晶状体外胚层（PLE）中条件性敲除小鼠Six3会破坏晶状体形成。在最严重的情况下，晶状体诱导和特化存在缺陷，晶状体基板和晶状体缺失。在Six3突变胚胎中，Pax6表达下调，晶状体前基板外胚层中Sox2缺失。通过染色质免疫沉淀、电泳迁移率变动分析和荧光素酶报告基因分析，我们确定Six3激活Pax6和Sox2的表达。将小鼠Six3错误表达于鸡胚中会促进外胚层Pax6表达域的异位扩展。我们的结果表明Six3处于导致晶状体形成的调控通路顶端。我们得出结论，Six3直接激活PLE中的Pax6，可能还激活Sox2，并自主调节哺乳动物晶状体诱导的最早阶段。
