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  • Review Article
  • Published:

Retinoid signalling in the development of the central nervous system

Nature Reviews Neuroscience volume 3, pages 843–853 (2002)Cite this article

Key Points

  • Vitamin A is an essential component of the diet; in its absence, animals show characteristic changes, including keratinization of epithelia, decreased immune function, anaemia and blindness. Dietary deficiency during pregnancy also causes congenital malformations in the embryonic central nervous system (CNS).

  • Retinoic acid (RA) is the most biologically active member of the retinoids — a family of molecules that are derived from vitamin A. RA is highly teratogenic when administered in excess to pregnant mammals, and it has been shown to cause patterning defects in the CNS.

  • The primary neurons in fish and amphibians coordinate escape movements, and their numbers are regulated by RA.

  • In addition to regulating the genes that control neuronal differentiation, RA switches on genes that pattern the neural plate along the anteroposterior (AP) axis. Initial experiments implied that it acts throughout the AP extent of the neural tube, but subsequent experiments have focused on a more localized role in the hindbrain and anterior spinal cord.

  • There are two theories to explain how RA organizes AP patterning. There could be a head-to-tail gradient, with a high point at the posterior end, or there could be a localized source of RA at the posterior end of the hindbrain. The existence of a gradient has proved difficult to demonstrate, and recent findings seem to point towards the latter model.

  • RA is also required for the patterning of neuronal populations along the dorsoventral axis of the neural tube. It seems to suppress ventral neuronal genes and to induce dorsal genes, allowing the generation of interneurons in the centre of the spinal cord. In addition, RA is required for the specification of lateral motor column neurons.

  • As RA is an essential component of the adult diet, it is likely that RA signalling also occurs in the adult. The failure of any component of the RA signalling pathway would be expected to cause a malfunction in the neurons concerned. Indeed, defects in RA signalling have been implicated in several neurological diseases, including movement disorders, schizophrenia and motor neuron disease.

Abstract

Retinoids — a family of molecules that are derived from vitamin A — have been implicated in many developmental processes. In the embryonic vertebrate central nervous system (CNS), retinoic acid (RA) has a role in patterning both the anteroposterior and dorsoventral axes. Initially, RA was thought to be involved in generating the entire anteroposterior extent of the CNS, but more recent experiments have identified its main sites of action as the hindbrain and anterior spinal cord. RA also regulates interneuron and motor neuron development along the dorsoventral axis. This review describes the studies that led to these conclusions, and discusses how understanding the mechanisms of RA action in the developing CNS might provide insights into neurological disease.

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Figure 1: Pathways for the synthesis and mechanism of action of RA.
Figure 2: Primary neurons in Xenopus and the effect of altered RA signalling.
Figure 3: Chart to show where RA fits into the scheme of neural development.
Figure 4: The effects of altered RA signalling on Xenopus embryos.
Figure 5: The effects of increasing and decreasing RA signalling on the hindbrain of chick and mouse embryos.
Figure 6: The hindbrain structure after gradually decreasing RA signalling.
Figure 7: Endogenous RA in the chick and mouse embryo.
Figure 8: Role of RA in the dorsoventral axis of the spinal cord.

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Authors and Affiliations

  1. MRC Centre for Developmental Neurobiology, 4th Floor New Hunt's House, King's College London, Guy's Campus, London Bridge, London, SE1 1UL, UK

    Malcolm Maden

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DATABASES

LocusLink

ADHs

CRABP1

CRABP2

CRBP1

CRBP2

CYP26A1

CYP26B1

Eph

MafB

Meis2

RALDH1

RALDH2

RALDH3

RARα

RARβ

RARγ

RoDHs

RXRα

RXRβ

RXRγ

OMIM

Parkinson's disease

schizophrenia

Swiss-Prot

CEK8

chordin

En2

follistatin

Gli3

Hoxb3

Hoxb4

Hoxb9

Krox20

noggin

Otx2

Pax2

Pax6

XASH-3

X-delta-1

X-MyT1

X-ngnr-1

X-shh

Zic2

FURTHER INFORMATION

Encyclopedia of Life Sciences

vertebrate central nervous system: pattern formation

Glossary

XEROPHTHALMIA

An excessive dryness of the conjunctiva and cornea.

HYDROCEPHALUS

A condition, marked by an expansion of the cerebral ventricles and a compression of neural structures, that is caused by a block in the flow of cerebral spinal fluid or by its overproduction.

SPINA BIFIDA

Failure of neural tube closure at the posterior neuropore, which causes the spinal cord tissue to protrude through the vertebral column.

ANOPHTHALMIA

Absence of the eyeballs.

MICROPHTHALMIA

A reduction in the size of the eyeballs.

EXENCEPHALY

Failure of the cranial component of the neural tube to close.

ENCEPHALOCOEL

A neural tube defect that causes the herniation of brain tissue.

MICROCEPHALY

An abnormally small head, caused by reduced growth of the brain or skull.

TAIL BUD

A blastema-like structure at the posterior end of the embryo that gives rise to all the structures of the sacrocaudal body region: neural tube, notochord, paraxial mesoderm and gut endoderm.

TERATOCARCINOMA CELLS

A cell line derived from a malignant germ-cell tumour, which arises from the ovary or testis and is composed of embryonal carcinoma cells.

NEUROBLASTOMA CELLS

An immortalized cell line derived from tumours that arise from the neural crest.

ANIMAL CAPS

An explant cut from an amphibian embryo at the blastula stage, comprising a 'cap' of about 60° that is centred on the animal pole. These explants consist of uncommitted ectodermal tissue, and they are often used to test the activities of putative neuralizing factors.

GASTRULATION

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

PRONEURAL GENES

Genes that encode transcription factors of the basic helix–loop–helix class that specify neural progenitor cells and promote their differentiation.

PREPATTERN GENES

Also known as pre-proneural genes, these genes seem to provide a link between the patterning of the nervous system and the specification of neurons.

BLASTULA

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

NEURULA

The stage of development that follows gastrulation, when the neural plate starts to develop from the ectoderm.

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.

OTOCYST

An ectodermal invagination that constitutes the primordium of the internal ear.

NODE

A major organizing centre in primitive-streak-stage embryos that regulates pattern formation. It is known as Hensen's node in chick and the Spemann organizer in frog.

PARAXIAL MESENCHYME

A region of the mesoderm adjacent to the notochord, which becomes segmented rostrocaudally to give rise to the somites early in development.

BRACHIAL

At the level of the forelimbs.

LUMBAR

At the level of the lower back.

SUBSTANTIA NIGRA

A part of the midbrain that contains dopamine-producing neurons, the axons of which innervate the striatum and thereby control body movements.

MORRIS WATER MAZE

A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the platform. Learning in this task involves the hippocampus.

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Maden, M. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci 3, 843–853 (2002). https://doi.org/10.1038/nrn963

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