Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Genes Dev. 2011 Sep 1;25(17):1783-95. doi: 10.1101/gad.17227011. Epub 2011 Aug 19.
Axial patterning of the embryonic brain requires a precise balance between canonical Wnt signaling, which dorsalizes the nervous system, and Sonic hedgehog (Shh), which ventralizes it. The ventral anterior homeobox (Vax) transcription factors are induced by Shh and ventralize the forebrain through a mechanism that is poorly understood. We therefore sought to delineate direct Vax target genes. Among these, we identify an extraordinarily conserved intronic region within the gene encoding Tcf7l2, a key mediator of canonical Wnt signaling. This region functions as a Vax2-activated internal promoter that drives the expression of dnTcf7l2, a truncated Tcf7l2 isoform that cannot bind β-catenin and that therefore acts as a potent dominant-negative Wnt antagonist. Vax2 concomitantly activates the expression of additional Wnt antagonists that cooperate with dnTcf7l2. Specific elimination of dnTcf7l2 in Xenopus results in headless embryos, a phenotype consistent with a fundamental role for this regulator in forebrain development.
胚胎大脑的轴向模式形成需要经典 Wnt 信号（使神经系统背侧化）和 Sonic hedgehog（Shh）（使它腹侧化）之间的精确平衡。Shh 诱导的腹侧前同源盒（Vax）转录因子通过一种机制使前脑腹侧化，而这种机制尚不清楚。因此，我们试图描绘直接的 Vax 靶基因。在这些基因中，我们在编码 Tcf7l2 的基因内鉴定出一个非常保守的内含子区域，Tcf7l2 是经典 Wnt 信号的关键介质。该区域作为 Vax2 激活的内部启动子发挥作用，驱动 dnTcf7l2 的表达，dnTcf7l2 是一种不能结合 β-连环蛋白的截断 Tcf7l2 同工型，因此作为一种有效的显性负 Wnt 拮抗剂起作用。Vax2 同时激活其他 Wnt 拮抗剂的表达，这些拮抗剂与 dnTcf7l2 合作。在 Xenopus 中特异性消除 dnTcf7l2 会导致无头胚胎，这种表型与该调节剂在大脑前部发育中的基本作用一致。
