Mechanism of fore-mid-brain determination by XSa1F

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The aim of this study is to understand molecular mechanisms of the early vertebrate embryo, particularly in the nervous system, by focusing on the roles of zinc-finger proteins and their related molecules in the rostral neuroectodermal development of Xenopus. We had previously isolated the zinc-finger factor XSa1F, which plays an essential role in the determination of the rostral brain. In this study, we identified another zinc-finger transcription factor, XTsh3, which is expressed in the Xenopus caudal nervous system. We showed that XTsh3 is a promoting factor required for the proper development of the caudal neural tissues. Overexpression of XTsh3 caused caudalization of the neural tissues and suppressed forebrain development. Conversely, XTsh3-MO injection, which blocks its function, enhanced forebrain development. In signaling analysis, we found that XTsh3 augments Wnt/b-catenin signaling. XTsh3 binds to both b-catenin and Tcf3, and amplifies Wnt-induced transcription. Consistent with these observations, XTsh3-MO injection into mesoendodermal tissues inhibited dorsal development, leading to strong ventralization of the whole embryo. Thus, in addition to XSa1F, which acts as a negative modulator of Wnt signaling, XTsh3 plays an important role in the fine modulation of the Wnt pathway. The antagonistic pair of XSa1F and XTsh3 is likely to function as a binary switching system of Wnt-On vs.-Off regulations.