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Neural induction, the default model and embryonic stem cells

Nature Reviews Neuroscience volume 3, pages 271–280 (2002)Cite this article

Key Points

  • Nervous system development has been the centre of attention for embryologists since Spemann and Mangold showed that the vertebrate nervous system can be induced by a region of the embryo termed the 'organizer'. Initially, neural-inducing signals of the organizer were thought to act in an instructive manner, but later experiments indicated a more indirect action — inhibition of the bone morphogenetic protein (BMP) pathway. This led to the 'default' model of neural induction, which proposes that in the absence of cell–cell signalling, ectodermal cells will adopt a neural fate.

  • An outstanding issue is whether BMP inhibition is required for neural induction, or whether other pathways are involved. The current evidence indicates that fibroblast growth factors (FGFs) and Wnts act as neural inducers, but whether these pathways can mediate neural induction independently of their effects on BMP signalling remains to be shown.

  • The strongest argument against the default model comes from the chick epiblast, where BMP inhibition by noggin- or chordin-producing cells is not sufficient to induce neural tissue in non-neural cells, whereas node grafts in this region result in neural tissue formation. However, it is plausible that the cell grafts do not inhibit the complete array of BMPs expressed in the gastrula ectoderm.

  • Genetic data from targeted mutations in the mouse and screens conducted in zebrafish have not revealed an essential requirement for any one gene in neural induction. Although genetic data has been used extensively to question the role of BMP inhibition, it can similarly be applied to other putative neural inducers. To show conclusively that BMP inhibition is not essential for neural induction, this pathway would have to be completely blocked within the ectodermal layer. More complicated genetic analyses, such as multiple knockouts or germ-layer-specific loss of function, will be required to address this issue.

  • Ultimately, we are interested in understanding whether the mechanisms that operate in model organisms also apply to the human species. Recent studies indicate that BMPs might regulate ectodermal fate decisions in mouse embryonic stem (ES) cells, and the isolation of human ES cells represents a new paradigm for studying the intricacies of neural induction in the context of human development.

Abstract

Neural induction represents the earliest step in the determination of ectodermal cell fates. In vertebrates, bone morphogenetic proteins (BMPs) act as signals of epidermal induction. The inhibition of the BMP signalling pathway in the ectoderm is the hallmark of neural-fate acquisition, and forms the basis of the default model of neural induction. BMP inhibition seems to take place through distinct mechanisms in different vertebrate species, including transcriptional regulation of BMP gene expression and clearance of BMP ligands by secreted inhibitors. Here, we discuss the role of fibroblast growth factors and Wnt proteins in neural induction and in the regulation of BMP signalling in the ectoderm of Xenopus laevis and chick embryos. In addition, we discuss evidence from mouse embryonic stem cells that supports the default model of neural induction and the role of BMP signalling in ectodermal fate determination.

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Figure 1: The default model of neural induction in Xenopus laevis.
Figure 2: BMP signalling and the specification of ectodermal fate.
Figure 3: Embryonic stem cells and the default model for neural induction.

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Acknowledgements

The authors thank P. Bhanot and E. Bell for helpful comments on the manuscript, and D. Benyaklef for the figure in box 1. This work was funded by a Helen Hay Whitney Foundation Fellowship to I.M.-S. and a National Institutes of Health grant to A.H.B.

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Authors and Affiliations

  1. Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, 10021, New York, USA

    Ignacio Muñoz-Sanjuán & Ali H. Brivanlou

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  1. Ignacio Muñoz-Sanjuán
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  2. Ali H. Brivanlou
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Correspondence to Ali H. Brivanlou.

Related links

Related links

DATABASES

FlyBase

dpp

sog

GenBank

activin receptor

BMP2

BMP4

BMP7

bozozok

cerberus

chordin

FGF2

FGF3

follistatin

GDF

HMG-X

noggin

OAZ

Ski

Smad1

Smad2

Smad4

Smad6

Smad7

Smad10

Smurf1

Smurf2

TGF-β

TSG

Wnt

Xnr3

LocusLink

Bmp2

Bmp4

Bmp7

BMPRs

cerberus 1

chordin

cystatin C

FGF2

FGFR

follistatin

HNF3-β

LIF

nestin

noggin

REST

Smad1

Smad4

Smad5

Smad6

Smad7

sonic hedgehog

TGF-β

Wnt

FURTHER INFORMATION

Brivanlou's lab

Encyclopedia of Life Sciences

BMP antagonists and neural induction

bone morphogenetic proteins and their receptors

cleavage and gastrulation in avian embryos

cleavage and gastrulation in mouse embryos

cleavage and gastrulation in Xenopus laevis embryos

mammalian embryo: Wnt signalling

signal transduction pathways in development: Wnts and their receptors

Spemann, Hans

Xenopus embryo: neural induction

Glossary

BLASTULA

An embryo before the gastrulation stage, consisting of a hollow ball of epithelial cells that surround a fluid-filled cavity.

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

CERBERUS

A secreted inhibitor of BMP, nodal and Wnt that has been implicated in head formation and anterior neural patterning.

NODAL

A ligand of the transforming growth factor-β family, secreted by the organizer, that signals through the Smad signal-transduction pathway.

MESENDODERM

Embryonic tissue that gives rise both to mesoderm and endoderm.

GASTRULATION

The process by which the embryo becomes regionalized into three layers: ectoderm, mesoderm and endoderm.

EPIBLAST

The outer layer of a blastula, which gives rise to the ectoderm after gastrulation.

PRE-STREAK

The earliest stage of gastrulation, before the appearance of the primitive streak.

CORTICAL ROTATION

Rotation of the cortex of the fertilized amphibian egg by ∼30° relative to the cytoplasm. It results in the displacement towards the equator, and subsequent activation, of factors that trigger the development of the organizer.

CEMENT GLAND

An amphibian organ that is situated anterior to the neural plate. Its development is sensitive to low levels of BMP signals.

ANTERIOR VISCERAL ENDODERM

An extra-embryonic organizing region in the mammalian embryo that is required for the induction of head structures.

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Muñoz-Sanjuán, I., Brivanlou, A. Neural induction, the default model and embryonic stem cells. Nat Rev Neurosci 3, 271–280 (2002). https://doi.org/10.1038/nrn786

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