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Development
2002 Dec 01;12923:5529-40. doi: 10.1242/dev.00097.
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Gene profiling during neural induction in Xenopus laevis: regulation of BMP signaling by post-transcriptional mechanisms and TAB3, a novel TAK1-binding protein.
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The earliest decision in vertebrate neural development is the acquisition of a neural identity by embryonic ectodermal cells. The default model for neural induction postulates that neural fate specification in the vertebrate embryo occurs by inhibition of epidermal inducing signals in the gastrulaectoderm. Bone morphogenetic proteins (BMPs) act as epidermal inducers, and all identified direct neural inducers block BMP signaling either intra- or extracellularly. Although the mechanism of action of the secreted neural inducers has been elucidated, the relevance of intracellular BMP inhibitors in neural induction is not clear. In order to address this issue and to identify downstream targets after BMP inhibition, we have monitored the transcriptional changes in ectodermal explants neuralized by Smad7 using a Xenopus laevis 5000-clone gastrula-stage cDNA microarray. We report the identification and initial characterization of 142 genes whose transcriptional profiles change in the neuralized explants. In order to address the potential involvement during neural induction of genes identified in the array, we performed gain-of-function studies in ectodermal explants. This approach lead to the identification of four genes that can function as neural inducers in Xenopus and three others that can synergize with known neural inducers in promoting neural fates. Based on these studies, we propose a role for post-transcriptional control of gene expression during neural induction in vertebrates and present a model whereby sustained BMP inhibition is promoted partly through the regulation of TGFbeta activated kinase (TAK1) activity by a novel TAK1-binding protein (TAB3).
Fig. 4. Whole-mount in situ hybridization of selected clones. (A) Clone 46-E2/FUSE-binding protein is expressed throughout the animal pole of the gastrulaembryo (left and center) and at tadpole stages in the branchial arches and the brain (right panel). (B) Clone 45-H5/prothymosin is expressed at high levels throughout the epithelial layer of the animal pole (left panel) and in anterior neural tissue both at neurula (middle panel) and tadpole stages (right panel). It is also seen in the tailbud (arrow in right panel). (C) Clone 47-B11/plexin, is expressed at gastrula stages throughout the animal pole (left panel). At neurula transcripts are detected throughout the spinal cord and neural tube. At tadpole stages, it is detected in the brain, spinal cord, the facial and trigeminal ganglia, and the pronephros (right). (D) Clone 47-F3/novel is expressed throughout the gastrulaembryo (left and center panels, arrow in middle panel depicts the dorsal blastopore lip). At later stages, expression is very strong in the brain and caudal end of the embryo (white arrows in right panel). It is also detected in ventraltissue (black arrow, right). (E) Clone 47-G3/hypothetical protein is strongly expressed in the animal pole at gastrula stages and in the dorsal blastopore lip (left). High levels are also detected in the nervous system and it is excluded from the cement gland (middle). At tadpole stages (right), it is expressed exclusively in the anterior neural tube. (F) Clone 51-A10/hypothetical protein is expressed at neurula stages in ciliated epidermal cells (arrows, left) and the presumptive otic placodes (arrow in center). In the tadpole (right), notice expression in the nervous system, branchial arches and pronephros. (G) Clone 51-D6/RNA bp EWS is expressed at high levels throughout the gastrulaembryo excluding the vegetal pole (left panel), expression is very high in the anterior neural plate at neurula (middle) and is then expressed throughout the brain at tadpole stage (right). (H) Clone 57-G10/TAB3 is expressed throughout both the embryo at both gastrula and neurula stages (left and middle). At tadpole stage, expression is seen in the brain and branchial arches (right). (I) Clone 47-G6/DG42 is expressed throughout the animal pole in the gastrula (left) and is excluded from the neural plate at neurula stages (center); by tadpole stage it is only expressed in ventral regions of the gut (right, see arrow). a, anterior; ba, branchial arches; cg, cement gland; fb, forebrain; hb, hindbrain; mb, midbrain; nc, notochord; np, neural plate; nt, neural tube; ov, otic vesicle; p, posterior; pn, pronephros; tb, tailbud; viith, facial ganglia; *, dorsal blastopore lip.
Fig. 6. Functional analysis of clones 56-G6/HMG-X and 57-G10/TAB3 in animal cap explants. (A) Clones 56-G6/HMG-X and 57-G10/TAB3 were injected into animal caps and analyzed for fate changes at stage 20. Both clones induce neural or cement gland marker expression. Notice no induction of posterior neural markers (En-2, mid/hindbrain; Krox-20, hindbrain; twist, neural crest) and weak induction of the heart marker xNkx2.5. (B) 56-G6/HMG-X synergizes with low amounts of Smad7 (5 pg). Notice inhibition of cement gland fates induced by Smad7 in the presence of 56-G6/HMG-X (lane 5). (C-H) Gain-of-function experiments with 56-G6/HMG-X in vivo. Embryos were injected into 1/2 cells in the animal pole and embryos analyzed at tadpole stages. Notice enlargement of the anterior neural plate (C-E), and ectopic expression of the anterior neural marker Pax6 (F-H). Asterisks indicate enlarged anterior neural territory (D,E) and ectopic Pax6 expression (G,H).
