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Specification of catecholaminergic and serotonergic neurons

Nature Reviews Neuroscience volume 3, pages 531–541 (2002)Cite this article

Key Points

  • The specification of neurotransmitter phenotype is an important aspect of neuronal fate determination. Here, we review our current knowledge of the regulatory circuits that direct neurotransmitter choice and the development of catecholaminergic — noradrenergic (NA) and dopaminergic (DA) — and serotonergic (5-hydroxytryptamine (5-HT, serotonin)-synthesizing) neurons.

  • In both the peripheral and central nervous systems, NA differentiation depends on bone morphogenetic protein (BMP) signalling and on the Mash1 and Phox2b transcription factors. In the sympathetic NA lineage, at least five transcription factors — Mash1, Phox2a, Phox2b, dHand and Gata3 — collaborate in the specification of the NA phenotype. The central NA neurons, which form a nucleus called the locus coeruleus, use many of the same factors, but in a different order.

  • Most DA neurons are located in the substantia nigra and ventral tegmental area of the midbrain. The induction of DA neurons depends on signals from the floor plate and the isthmus, including sonic hedgehog (Shh) and fibroblast growth factor 8 (FGF8). Specification and maintenance of midbrain DA neurons depends on the Nurr1 and Lmx1b transcriptional regulators.

  • 5-HT neurons arise from ventral neuroepithelial progenitors close to the floor plate. Their development, like that of DA neurons, depends on previous patterning of the neuroepithelium by Shh and FGF signalling. At least three transcriptional regulators — Nkx2.2, Gata3 and Pet1 — are required for 5-HT-neuron development.

  • The available data are compatible with a model in which different neuronal types use distinct combinations of transcription factors to control not only the expression of shared properties, such as transmitter-synthesizing enzymes, but also the expression of generic neuronal properties.

Abstract

The specification of neurotransmitter phenotype is an important aspect of neuronal fate determination. Substantial progress has been made in uncovering key extracellular signals and transcriptional regulators that control the mode of neurotransmission in several model systems, among which catecholaminergic and serotonergic neurons feature prominently. Here, we review our current knowledge of the regulatory circuits that direct neurotransmitter choice, and discuss the development of well-studied types of catecholaminergic and serotonergic neurons. One emerging concept is that different types of neuron use a similar core programme to control shared modes of neurotransmission, but recruit different factors that are specific for each neuronal type. Another is that most factors that specify neurotransmitter identity also control other features of the neuronal phenotype.

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Figure 1: Enzymatic pathways of catecholamine and 5-HT synthesis.
Figure 2: Location of 5-HT, locus coeruleus and midbrain dopaminergic neurons with respect to sources of important signalling molecules.
Figure 3: Migration pathway and location of sympathetic precursors.
Figure 4: Cell-extrinsic and -intrinsic factors that are known to be involved in the generation of noradrenergic, dopaminergic and 5-HT neurons.
Figure 5: Regulatory network controlling sympathetic-neuron development.
Figure 6: Transcription-factor cascade controlling locus coeruleus development.

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Acknowledgements

We thank E. Deneris, J. Ericson, M. Howard and A. Pattyn for disclosing unpublished results, and J.-F. Brunet, F. Müller and M. Stanke for helpful comments on the manuscript. The work carried out in the authors' laboratories was supported by grants to H.R. from the Deutsche Forschungsgemeinschaft, the Fonds der chemischen Industrie and the European Community (QLG3-CT-2000-0072), and by grants to C.G. from the European Community (QLGT-CT-2001-01467), the Association Française contre les Myopathies and the Ministère de la Recherche.

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  1. Département de Biologie, CNRS UMR 8542, École Normale Supérieure, 46 rue d'Ulm, Paris, 75230 Cedex 05, France

    Christo Goridis

  2. Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Deutschordenstr. 46, Frankfurt/Main, 60528, Germany

    Hermann Rohrer

Authors
  1. Christo Goridis
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  2. Hermann Rohrer
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Corresponding author

Correspondence to Christo Goridis.

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DATABASES

GenBank

BMP5

FGF4

FGF8

Foggy

Smad5

LocusLink

Aldh1

BMP2

BMP4

BMP7

DAT

DBH

dHand

En1

En2

Gata3

Gli2

Lmx1b

Mash1

NET

NF160

Nkx2.2

noggin

Nurr1

Pet1

Phox2a

Phox2b

Pitx3

Ret

Rnx

RXR

SCG10

SERT

Shh

TH

tryptophan hydroxylase

OMIM

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

adrenaline and noradrenaline

amine neurotransmitters

amine transporters

dopamine

serotonin

Glossary

SYMPATHETIC NEURONS

The neurons of the sympathetic nervous system, which is responsible for such physiological effects as reduction of digestive secretions, vasoconstriction and increased heart rate, thereby opposing the effects of the parasympathetic nervous system.

RAPHE NUCLEI

A series of neuronal groups located along the midline of the brainstem. They constitute the main supply of 5-hydroxytryptamine to the rest of the brain.

NEURAL CREST

Groups of cells that migrate from the neural tube to the periphery, where they give rise to a wide variety of cell types.

BONE MORPHOGENETIC PROTEINS

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

BASIC HELIX–LOOP–HELIX

(bHLH). A structural motif that is present in many transcription factors, which is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

PRONEURAL GENES

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

HOMEODOMAIN

A 60-amino-acid DNA-binding domain that comprises three α-helices and is found in many transcription factors.

ZINC FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.

AUTONOMIC NEURON

A neuron that belongs to the part of the nervous system that is not under conscious control, and regulates functions such as breathing, circulation and digestion.

ROOF PLATE

The point of fusion of the neural folds, which forms the dorsal-most part of the neural tube.

ISTHMUS

A narrow section of the neural tube that separates the midbrain from the hindbrain.

FLOOR PLATE

The ventral cells of the neural tube that lie along the midline.

MYELENCEPHALON

The caudal subdivision of the embryonic hindbrain, which gives rise to the medulla oblongata.

ETS DOMAIN

The DNA-binding domain of the transcription factors of the Ets family, so-called after the avian ets1 proto-oncogene.

CHIMERIC MICE

Mice that are genetically mosaic. They are produced mainly by injecting embryonic stem (ES) cells of one genotype into blastocysts of another genotype, resulting in mice whose cells are partly derived from the ES cells and partly from the host blastocyst.

BRANCHIOMOTOR NEURONS

The neurons of the cranial nerves that control muscles derived from the branchial arches. In humans, they are the trigeminal, the facial, the glossopharyngeal, the vagus and the spinal accessory nerves.

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Goridis, C., Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat Rev Neurosci 3, 531–541 (2002). https://doi.org/10.1038/nrn871

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