Sasai Y and De Robertis EM (1997), Ectodermal patterning in vertebrate embryos.

XB-ART-16951

Dev Biol 1997 Feb 01;1821:5-20. doi: 10.1006/dbio.1996.8445.

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Ectodermal patterning in vertebrate embryos.

Sasai Y , De Robertis EM .

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Recent molecular insights on how the ectodermal layer is patterned in vertebrates are reviewed. Studies on the induction of the central nervous system (CNS) by Spemann's Organizer led to the isolation of noggin and chordin. These secretory proteins function by binding to, and inhibiting, ventral BMPs, in particular BMP-4. Neural induction can be considered as the dorsalization of ectoderm, in which low levels of BMP-signaling result in CNS formation. At high levels of BMP signaling the ectoderm adopts a ventral fate and skin is formed. In Xenopus the forming neural plate already has extensive dorsal-ventral (D-V) patterning, and neural induction and D-V patterning may share common molecular mechanisms. At later stages sonic hedgehog (shh) plays a principal role in D-V patterning, particularly in the neural tube of the amniote embryo. A great many transcription factor markers are available and mouse knockouts provide evidence of their involvement in the regional specification of the neural tube. Recent evidence indicating that differentiation of posterior CNS is promoted by FGF, Wnt-3a, and retinoic acid is reviewed from the point of view of the classical experiments of Nieuwkoop that defined an activation and a transformation step during neural induction.

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Species referenced: Xenopus
Genes referenced: ascl2 bmp4 chrd dspp fgf4 foxa2 fst lhx1 lhx3 msx1 ncam1 nog shh tbx2 tbxt wnt3a

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	FIG. 1. Dorsal and ventral signals change the fate of tissues by providing varying dorsalâ ventral positional information (Sasai et al., 1995). (A) The dorsal signals from the frog organizer, chordin, noggin, and follistatin (XFS) act on both marginal zone cells (meso-dermal precursors) and animal cap cells (ectodermal precursors) and induce dorsal-type tissues: dorsal mesoderm (notochord and muscle) and neural tissues, respectively. Ventral signals such as BMP-4 also change the fate of both mesodermand ectoderm, gener-ating ventral mesoderm (blood, mesothelium, and mesenchyme) and epidermis. Thus, the same set of antagonizing regulatory signals, the organizer factors vs BMP-4, can pattern both germ layers.
	FIG. 2. Experiment by Cunliffe and Smith (1994) illustrating how a differential response to the same signal can be generated. Animalcaps treated with noggin became neural. When animal caps were injected with Xbra, a mesoderm-specific transcription factor, the explants became dorsal mesoderm in response to the same noggin signal.
	FIG. 3. The organizer factors inactivate BMP-4 by binding it in the extracellular space. Both chordin and noggin bind to BMP-4 and inhibit BMP-4 protein from binding to its own receptor. Down-stream of the BMP receptor, the vertebrate homologue of Drosoph-ila mother against dpp (MAD) seems to play a fundamental role in the signal transmission to the nucleus. Among the target genes in the BMPR signaling pathways are ventral-specific homeodomain (HD) proteins. Both MAD and ventral HD factors can mimic the ventralizing activity of BMP-4 by microinjection.
	FIG. 4. Expression of gene markers during early patterning. (A) Whole-mount in situ hybridization of N-CAM in the early Xenopus neurula. The N-CAM staining demarcates the early neural plate. Note that the presumptive floor plate is devoid of N-CAM transcript, indicating that the floor plate has a distinct pattern of differentiation that can be traced back to this early stage. (B) Double labeling in situ hybridization of chordin (brown) and the neuronal marker b-tubulin (blue) at the early neurula. Chordin expression is detected in axial mesoderm (notochord) and the initial D-V arrangement of the primary neurons has already been established by the neural plate stage. m, medial neurons (motoneurons); i, intermediate neurons (interneurons); l, lateral neurons (Rohon-Beard neurons). These neurons are involved in the escape reflex of the tailbud tadpole. V, trigeminal ganglion. (C) Schematic map of the early D-V arrangement of the ectoderm at the neural plate stage in Xenopus. In the neural plate (from medial to lateral), the presumptive floor plate (FP), the motoneuron (MN), and intermediate neurons (IMN) are found. The trunk neural plate is flanked by the presumptive neural crest (hatched area) while in the head the placode-forming region (black area) borders the neural plate. In the posterior, sensory Rohon-Beard neurons (RBN) form in the ectoderm just outside of the neural plate. Photographs kindly provided by Bin Lu.
	FIG. 5. Diagram of how the initial neural induction and D-V patterning of the neural tube might share common mechanisms. At the early neurula, BMP-4 in the ventral ectoderm and mesoderm is antagonized by chordin, noggin, and follistatin (XFS), which are secreted by dorsal chordamesoderm derived from Spemannâs organizer (notochord, blue, and somite, yellow). These signals could pattern the ectoderm forming floor plate (thick black layer), neural plate (pink), and neural crest (orange) at different concentrations. At high BMP-4 concentrations BMP-4 leads to skin development (ventral ectoderm). At the late neurula stage (left), the notochord and floor plate produce the shh signal, which is opposed by a number of BMP-related molecules expressed in the dorsal neural tube and nearby ectoderm.
	FIG. 6. Transcription factors involved in the D-V specification of the CNS in amniotes. On the left half of the scheme, the differential expression of seven Pax genes is indicated (modified after Gruss andWalther, 1992). Other classes of transcription factors are shown on the right half, including Msx-1/2 (roof plate and neural crests), lim-1 (alar plate), lim-3 (basal plate), isl-1/2 (motoneurons), Xash3 (sulcus limitans), Nkx 2.2 (region between the floor plate and moto neurons, area of expression varies slightly among species), and HNF-3b (floor plate). Many of these transcription factors have been shown to play essential roles in the development of the regions that express them (see text).
	FIG. 7. Schematic models for the formation of posterior CNS. (A) A two inducer model. The archencephalic and deuterencephalic inducers promote the formation of anterior CNS and posterior CNS, respectively. The concentration gradient and/or combination of the two kinds of inducers determine the fine pattern. In the context of our discussion, the two inducer model stands for the existence of posterior neural inducers that can directly initiate posterior-type neural differentiation from presumptive ectodermal tissues. (B) The two step model. First, the neural inducers initiate neural differentiation of the ectoderm. The neural inducers, when acting alone, promote formation of archencephalic neural tissues. In a second transformation step, posteriorizing factors act on the induced neural tissue and give various posterior values depending on concentration timing. (C) A possible model for the involvement of known inducers and modulators. The dorsal mesoderm releases chordin, noggin, and follistatin (XFS), which can act as archencephalic neural inducers. The posterior mesoderm expresses FGFs (e.g., eFGF), Wnts (e.g., Wnt3a), and contains RA.