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WIREs Dev Biol
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Neural induction and early patterning in vertebrates

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Abstract In vertebrates, the development of the nervous system is triggered by signals from a powerful ‘organizing’ region of the early embryo during gastrulation. This phenomenon—neural induction—was originally discovered and given conceptual definition by experimental embryologists working with amphibian embryos. Work on the molecular circuitry underlying neural induction, also in the same model system, demonstrated that elimination of ongoing transforming growth factor‐β (TGFβ) signaling in the ectoderm is the hallmark of anterior neural‐fate acquisition. This observation is the basis of the ‘default’ model of neural induction. Endogenous neural inducers are secreted proteins that act to inhibit TGFβ ligands in the dorsal ectoderm. In the ventral ectoderm, where the signaling ligands escape the inhibitors, a non‐neural fate is induced. Inhibition of the TGFβ pathway has now been demonstrated to be sufficient to directly induce neural fate in mammalian embryos as well as pluripotent mouse and human embryonic stem cells. Hence the molecular process that delineates neural from non‐neural ectoderm is conserved across a broad range of organisms in the evolutionary tree. The availability of embryonic stem cells from mouse, primates, and humans will facilitate further understanding of the role of signaling pathways and their downstream mediators in neural induction in vertebrate embryos. WIREs Dev Biol 2012, 2:479–498. doi: 10.1002/wdev.90 This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Early Embryonic Development > Gastrulation and Neurulation Nervous System Development > Vertebrates: General Principles

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Fate map of the anterior border of the neural plate in Xenopus embryos. Schematic of dorsal–anterior (head‐on) view of a Xenopus neurula (the ventral side is up, and the dorsal side is down). Different colors highlight different fates.

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Signaling pathways involved in pluripotency and induction of neural fate in human embryonic stem cells (hESCs) by a ‘default’ mechanism. The three pathways mediating pluripotency in primed pluripotent cells, i.e., Activin/Nodal‐SMAD2/3, FGF‐MEK, and WNT‐β‐catenin, may repress neural fate directly and indirectly via pluripotency genes like NANOG. In addition, all these pathways can promote alternate non‐neural fates at higher thresholds of signaling, as denoted by thick lines. These non‐neural fates in turn also repress neural fate genes. Inhibition of TGFβ and BMP signaling by secreted proteins (such as Lefty and Noggin) or small molecules (SB431542 and LDN193189) are sufficient to convert pluripotent hESCs to a neural fate. Hence, the state of pluripotency requires overcoming of the default neural state. Arrows represent activation (shown as proportional to the thickness of the lines), whereas hatches represent inhibition. Dotted lines denote postulated mechanisms from evidence in non‐human systems.

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Schematic of graded BMP activity in the gastrula and neurula ectoderm. (a) A schematic fate map of the early gastrula shows the approximate positions of the future neural plate (NP), border region, and epidermis, viewed from the dorsal side. The cement gland (CG) and sensory placodes form in the anterior border region mid‐dorsally, whereas the neural crest arises more laterally. Diffusible antagonists produced in the organizer region of the mesoderm, including noggin, chordin, and follistatin, result in a graded distribution of BMP signaling in the neighboring ectoderm. The relative position of epidermis (EP), NP, organizer (O, in blue), CG, and neural crest (NC) is shown. Sensory placodes form at various positions in the border region but are not shown here for simplicity. (b) Correlation with neurula fate map shown in Figure 1.

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The transforming growth factor‐β (TGFβ) pathway. More than 30 different TGFβ ligands are encoded in the vertebrate genome. They include members of BMPs, GDFs, Activins, Nodal, and TGFβs, all of which activate the TGFβ pathway. The activity of these ligands is regulated by a large number of secreted inhibitory factors (Table ) that inhibit TGFβ signaling extracellularly. Upon secretion, homodimer or heterodimer of TGFβ ligands that escape inhibition bind to TGFβ receptors at the cell membrane. Ligands act as morphogens exerting diverse cellular responses based on the levels and duration of signaling. Dimeric TGFβ ligands bind type II receptors that phosphorylate and activate type I receptors in a heterotetrameric complex. Receptor activation, in turn, leads to the propagation of signaling by at least two pathways involving Smad (in the canonical pathway) or Traf/TGFβ‐Activated‐Kinase‐1 (TAK1, in the non‐canonical pathway). In the canonical pathway, a type I receptor propagates the signal by phosphorylating serine residues located at the C‐terminus of receptor‐Smads (R‐Smads). Two groups of R‐Smads transduce signals: R‐Smads 2/3 (from Activins/Nodals and TGFβ1/2/3) and R‐Smad1/5/8 (from BMP2/4/7 and some GDFs). R‐Smads are part of a trimeric complex with a common mediator Smad—called co‐Smad4—that translocates to the nucleus to regulate transcription via transcription factors. As in the extracellular space, a series of inhibitors influences input from TGFβ signaling inside the cell at multiple levels. At the membrane level, coreceptors, such as Bambi, EGF‐CFCs, and Tomoregulins, regulate the activity and selectivity of TGFβ receptor transduction. Downstream of receptor activation, inhibitory influences on R‐Smads occurs by linker phosphorylation via MAPK, GSK3β, and CDKs, providing connections between TGFβ and other signaling pathways. TGFβ signaling itself also has the ability to phosphorylate the R‐Smad linker. Linker phosphorylation leads to either degradation via ubiquitination by Smurf1/2 or changes in R‐Smad specificity of gene regulation. Smad6 and Smad7 provide another level of inhibition. Smad6 acts in a BMP‐dependent manner to compete with Smad4 binding and inhibit nuclear translocation of Smad1/5/8, whereas Smad7 acts in a ligand‐independent manner to inhibit the pathway at multiple levels, including downstream of the activated type I receptor. Finally, dephosphorylation of the C‐terminal end of R‐Smads, by phosphatases such as small C‐terminal domain phosphatases, has also been shown to downregulate the signal. The YAP/TAZ complex regulates Smad nuclear translocation and connects to the Hippo pathway. The non‐canonical TGFβ pathway is not as well understood; however, type II TGFβ receptors have been shown to signal through the Traf/TAK1 proteins. TAK1, in turn, activates JNK, p38, and MEK and the NF‐κβ pathway. As TAK1 can also be activated by a variety of cytokines, the WNT pathway, and the MAPK pathway, it provides yet another integration site for crosstalk amongst different signaling pathways.

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Nervous System Development > Vertebrates: General Principles
Signaling Pathways > Global Signaling Mechanisms
Early Embryonic Development > Gastrulation and Neurulation