Rasmussen J T, Deardorff M A, Tan C, Rao M S, Klein P S, Vetter M L
Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3861-6. doi: 10.1073/pnas.071586298.
Eye development in both invertebrates and vertebrates is regulated by a network of highly conserved transcription factors. However, it is not known what controls the expression of these factors to regulate early eye formation and whether transmembrane signaling events are involved. Here we establish a role for signaling via a member of the frizzled family of receptors in regulating early eye development. We show that overexpression of Xenopus frizzled 3 (Xfz3), a receptor expressed during normal eye development, functions cell autonomously to promote ectopic eye formation and can perturb endogenous eye development. Ectopic eyes obtained with Xfz3 overexpression have a laminar organization similar to that of endogenous eyes and contain differentiated retinal cell types. Ectopic eye formation is preceded by ectopic expression of transcription factors involved in early eye development, including Pax6, Rx, and Otx2. Conversely, targeted overexpression of a dominant-negative form of Xfz3 (Nxfz3), consisting of the soluble extracellular domain of the receptor, results in suppression of endogenous Pax6, Rx, and Otx2 expression and suppression of endogenous eye development. This effect can be rescued by coexpression of Xfz3. Finally, overexpression of Kermit, a protein that interacts with the C-terminal intracellular domain of Xfz3, also blocks endogenous eye development, suggesting that signaling through Xfz3 or a related receptor is required for normal eye development. In summary, we show that frizzled signaling is both necessary and sufficient to regulate eye development in Xenopus.
在无脊椎动物和脊椎动物中，眼睛的发育均受一系列高度保守的转录因子网络调控。然而，目前尚不清楚是什么控制这些因子的表达以调节早期眼睛形成，以及跨膜信号传导事件是否参与其中。在此，我们确立了通过卷曲蛋白家族受体成员进行信号传导在调节早期眼睛发育中的作用。我们发现，非洲爪蟾卷曲蛋白3（Xfz3），一种在正常眼睛发育过程中表达的受体，其过表达能自主发挥作用促进异位眼的形成，并可扰乱内源性眼睛发育。Xfz3过表达所形成的异位眼具有类似于内源性眼睛的分层结构，并包含分化的视网膜细胞类型。在异位眼形成之前，参与早期眼睛发育的转录因子，包括Pax6、Rx和Otx2会出现异位表达。相反，靶向过表达由受体的可溶性细胞外结构域组成的Xfz3显性负性形式（Nxfz3），会导致内源性Pax6、Rx和Otx2表达受到抑制以及内源性眼睛发育受到抑制。这种效应可通过共表达Xfz3来挽救。最后，过表达与Xfz3的C端细胞内结构域相互作用的蛋白Kermit，也会阻断内源性眼睛发育，这表明通过Xfz3或相关受体进行信号传导是正常眼睛发育所必需的。总之，我们表明卷曲蛋白信号传导对于调节非洲爪蟾的眼睛发育既是必要的也是充分的。
