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  • Review Article
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Initial patterning of the central nervous system: How many organizers?

Nature Reviews Neuroscience volume 2, pages 92–98 (2001)Cite this article

Abstract

For three-quarters of a century, developmental biologists have been asking how the nervous system is specified as distinct from the rest of the ectoderm during early development, and how it becomes subdivided initially into distinct regions such as forebrain, midbrain, hindbrain and spinal cord. The two events of 'neural induction' and 'early neural patterning' seem to be intertwined, and many models have been put forward to explain how these processes work at a molecular level. Here I consider early neural patterning and discuss the evidence for and against the two most popular models proposed for its explanation: the idea that multiple signalling centres (organizers) are responsible for inducing different regions of the nervous system, and a model first articulated by Nieuwkoop that invokes two steps (activation/transformation) necessary for neural patterning. As recent evidence from several systems challenges both models, I propose a modification of Nieuwkoop's model that most easily accommodates both classical and more recent data, and end by outlining some possible directions for future research.

Key Points

  • Different models have been proposed to explain the early patterning of the nervous system; among these, two have proved the most popular. On the one hand, the idea that there are separate organizers for the head and for the trunk/tail regions. On the other hand, the hypothesis first proposed by Nieuwkoop, which argues that neural patterning requires two steps: an activation step, in which neural fate is induced and the forebrain is specified; and a transformation step, in which some cells receive other signals from the organizer and acquire a caudal character.

  • Initial evidence favoured the existence of separate organizers; however, other findings have indicated that there might be a single region responsible for the direct induction of the forebrain or the head. Similarly, some evidence has lent support to Nieuwkoop's model, but a series of observations are incompatible with the two steps proposed by the model

  • As the two models are incompatible with each other, some experimental observations have been interpreted in terms of a mixture of both models. Indeed, recent results indicate that a modification of Nieuwkoop's model can successfully explain early neural patterning. In the new model, the chick hypoblast (and mouse anterior visceral endoderm, AVE) induces the transient expression of early neural and forebrain markers, thereby marking the cells that have been activated (as in Nieuwkoop's model). Then, maintenance signals are required for this state to be stabilized. Subsequently, some cells respond to the posteriorizing influence of the node and acquire a caudal phenotype. Furthermore, besides inducing the transient expression of early neural markers, the hypoblast/AVE also directs the anterior movement of the activated cells away from the influence of the node.

  • If the hypoblast/AVE transiently induces the expression of forebrain markers, what are the maintenance signals? What tissues are responsible for emitting the signals in amphibian embryos, which lack a structure equivalent to the hypoblast? When and how does the trunk nervous system become subdivided further? Although the new model accounts for the available evidence, these and many other questions still await an answer.

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Figure 1: Otto Mangold's experiment8.
Figure 2: Mouse and chick structures with proposed inducing functions.
Figure 3: Nieuwkoop's activation–transformation model48.
Figure 4: A modification of Nieuwkoop's model for neural induction and patterning.

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Acknowledgements

This review is dedicated to Rosa Beddington, who inspired so many, including myself, to think deeply about patterning of the nervous system. Although I have tried to provide a balanced view by incorporating data from many different model systems, I am unable to do justice to the work of many researchers, to whom I must apologize. The recent research of my group on this topic was funded by grants from the National Institutes of Mental Health (USA) and the Medical Research Council (UK).

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

    Claudio D. Stern

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DATABASE LINKS

Nodal

Otx2

Lim1

Hesx1

Hex

Sox3

FGFs

Wnt3A

ERNI

Sox1

Glossary

GASTRULA

Embryonic stage at which the embryo becomes three-layered, forming the mesoderm and definitive (gut) endoderm.

SENSORY PLACODE

A thickened region of ectoderm that will later give rise to a sensory organ.

EPIBLAST

One of the layers of cells in the early embryo, which gives rise to the skin and nervous system.

PRIMITIVE STREAK

An elongated depression of reptile, bird and mammalian embryos, through which mesodermal and endodermal cells migrate into the interior of the embryo. The most anterior tip of the primitive streak forms Hensen's node. The streak is functionally homologous to the amphibian blastopore.

PRECHORDAL MESENDODERM

A tissue derived from the node, lying at the rostral tip of the head process (notochord). The mesodermal component will give rise to some eye muscles.

URODELE

Order of amphibians, including salamanders and newts, in which the larval tail persists in the adult.

PROSENCEPHALON

The most rostral of the primary vesicles present in the early neural tube, which later gives rise to two secondary vesicles: telencephalon (prospective cerebral hemispheres) and diencephalon (prospective thalamus and hypothalamus).

NEURULA

Stage of development following gastrulation, when the neural plate starts to form from the ectoderm.

BONE MORPHOGENETIC PROTEINS

Secreted proteins of the transforming growth factor-β superfamily. In the early embryo, they participate in dorsoventral patterning.

DOMINANT-NEGATIVE PROTEIN

A mutant molecule that forms heteromeric complexes with the wild type to yield a non-functional complex.

AREA OPACA

A peripheral ring of the early avian blastoderm, which only gives rise to extra-embryonic tissues.

ANIMAL CAP

An explant cut from an amphibian embryo at the blastula stage, comprising a 'cap' of about 60° centred on the animal pole.

NOTOCHORD

Rod-like structure of mesodermal origin in vertebrates, which provides rigidity to the early embryo and will later contribute to the vertebral centra and intervertebral disks.

TELEOST

Group of fish with bony skeletons.

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Stern, C. Initial patterning of the central nervous system: How many organizers? . Nat Rev Neurosci 2, 92–98 (2001). https://doi.org/10.1038/35053563

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