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First published online April 13, 2005
doi: 10.1242/10.1242/dev.01794

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Neural induction: old problem, new findings, yet more questions

Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK

View larger version (14K): [in a new window]   Fig. 1. The `default model' in Xenopus. (A) A rough fate map of a blastula-stage embryo. Prospective territories are organizer in red, ventral mesoderm in pink, neural tissue in blue, epidermis in yellow and yolky endoderm in green. The red lines represent BMP antagonist activity emanating from the organizer. (B) A `genetic' diagram of the inductive interactions proposed by the model: ectoderm cells have an autonomous tendency to differentiate into neural tissue, but are prevented from doing this and are directed instead to epidermis by BMP4, which is expressed ubiquitously. Near the organizer, BMP antagonists block BMP4 signalling, allowing neighbouring ectoderm cells to develop according to their `default' neural fate. D, dorsal; V, ventral. Modified, with permission, from Stern (Stern, 2004).

View larger version (35K): [in a new window]   Fig. 2. Experiments in Xenopus that support the default model. (A) Cell-dissociation experiments (results shown in the two left-most columns in the table) and intact animal cap assays with or without BMP antagonists (antag.) (results shown in the third and fourth columns). -Ca2+, Mg2+ indicates that the protein was applied in low Ca2+/Mg2+ medium. (B) In the most common type of animal cap experiment, a two- to four-cell stage embryo is injected with RNA encoding a protein to be tested (here, BMP antagonists: DNBMPR, dominant-negative BMP receptor; Nog, Noggin; Chd, Chordin; Smad6, the inhibitory effector Smad6). After incubating the embryo to the blastula stage, the animal cap is excised and grown in isolation overnight before assessing its marker gene expression. The table shows the usual results of these experiments: + indicates expression of markers for the tissue shown; - indicates no expression; arrows indicate downregulation;? indicates a fate that has not been tested in published experiments. Modified, with permission, from Stern (Stern, 2004).

View larger version (72K): [in a new window]   Fig. 3. Chick organizer graft experiments. (A-C) Chick organizer graft experiments showing changes in inducing ability with increasing age of the donor. (A,C) Dorsal views of early quail donor embryos. (B) Dorsal view of host chick embryo, which simultaneously receives a graft of a quail stage 4 node on its left and a quail stage 6 node on its right. Both grafts are placed in the extra-embryonic area opaca (brown), just outside the embryonic area pellucida (yellow). (D) Results of this experiment after in situ hybridization for the hindbrain marker Krox20 (purple), which is expressed in rhombomeres 3 and 5 (upwards arrow), and after staining with an anti-quail antibody (reddish-brown). The young (stage 4) graft has induced a complete axis including the head (expressing Krox20), while the older graft on the right has generated a short axis, mostly derived from the graft itself (reddish-brown indicating quail cells), which lack rostral structures, including the hindbrain (Krox20-expressing region). (A-C) Modified, with permission, from Stern (Stern, 2004). (D) Reproduced, with permission, from Storey et al. (Storey et al., 1992).

View larger version (20K): [in a new window]   Fig. 4. Two models of neural induction. Models based on studies in (A) Xenopus and (B) chick, proposed to reconcile findings on the roles of BMP, FGF and Wnt signalling in neural induction. (A) In this model, at the late blastula/early gastrula stage, FGF signalling cooperates with BMP inhibition to induce a neural (blue) fate by inhibiting Smad1 phosphorylation, repressing Bmp transcription, and inducing expression of the BMP antagonists Chordin (Chd) and Noggin (Nog). At low levels, FGF seems to induce a neural fate directly. High BMP activity induces epidermis (yellow), while high FGF signalling cooperating with Nodal-related factors (XNRs) induces mesoderm (red). At earlier (pre-blastula) stages, Fgf, Xnrs, Bmp, Chd and Nog distribution are determined by both the nuclear localisation of ß-catenin (orange dots) and the vegetal localisation of the T-box transcription factor VegT (purple dots), which pattern the early embryo. Modified, with permission, from Delaune et al. (Delaune et al., 2005). (B) An alternative but similar model (Wilson and Edlund, 2001) from explant experiments in chick. At the blastula stage, medial epiblast cells (prospective neural cell) express FGFs but not Wnts. FGF signalling activates two transduction pathways in epiblast cells: repression of BMP expression and the promotion of neural fate by an independent pathway (broken line from FGF). Lateral epiblast cells (prospective epidermal cell) express both FGFs and Wnts. High Wnt levels block the response of epiblast cells to FGFs, BMPs are expressed, and BMP signals promote epidermal fate and repress neural fate. When Wnt signalling is attenuated, Wnts block the ability of FGFs to repress BMP expression, but the independent pathway (broken line) promoting neural fate is preserved. Under these conditions, BMP antagonists are able to induce neural fate. Modified, with permission, from Wilson and Edlund (Wilson and Edlund, 2001).

View larger version (32K): [in a new window]   Fig. 5. A model of Churchill functions and regulation during early development in chick. (A-D) The embryologist's view, showing embryos at four stages, viewed obliquely from the dorsal side (posterior towards the right), with their germ layers teased apart (brown represents hypoblast, yellow the epiblast). (A) Stages XI-XII. The hypoblast emits FGF8, which induces the early pre-neural genes ERNI and SOX3 (orange) in the overlying epiblast (yellow). At this stage, cells in this domain are still uncommitted. Nodal is expressed in the posterior epiblast but is inhibited by Cerberus secreted by the hypoblast. (B) Stages XIII-2. The hypoblast is displaced from the posterior part of the embryo by the endoblast (white), which allows Nodal signalling, in synergy with FGF, to induce Brachyury (Bra) and Tbx6L and ingression (red arrows) to form the primitive streak (red, its position is outlined with a broken line in the epiblast layer). (C) Stages 3+-4. Continued FGF signalling now induces churchill in a domain of the epiblast (light blue). The border of the epiblast territory destined to ingress to form mesoderm is shown with a broken black line. (D) At the end of stage 4, churchill induces SIP1, which blocks Bra, Tbx6L and further ingression of epiblast into the anterior streak. The epiblast remaining outside the streak (blue) is now sensitized to neural-inducing signals emanating from the node (blue arrows). (E) The same model as a genetic cascade. Black represents interactions described by Sheng et al. (Sheng et al., 2003). Grey indicates other interactions from published data. The time axis (right) shows time in hours after a graft of Hensen's node, and the colour gradients indicate progressive commitment to epidermis (yellow), neural (blue) and mesoderm (red). BMP/Smad/Sip1 interactions regulate the epidermis-neural plate border, while ChCh/Sip1/FGF/Bra/Tbx6 regulate the mesoderm-neural decision. The asterisk indicates phosphorylated Smad1.??? represents as yet unknown components. Modified, with permission, from Sheng et al. (Sheng et al., 2003).

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