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Ascl1/Mash1 is required for the development of central serotonergic neurons

Nature Neuroscience volume 7, pages 589595 (2004) | Download Citation

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Abstract

The transcriptional control of the differentiation of central serotonergic (5-HT) neurons in vertebrates has recently come under scrutiny and has been shown to involve the homeobox genes Nkx2-2 and Lmx1b, the Ets-domain gene Pet1 (also known as Fev) and the zinc-finger gene Gata3. The basic helix-loop-helix (bHLH) gene Ascl1 (also known as Mash1) is coexpressed with Nkx2-2 in the neuroepithelial domain of the hindbrain, which gives rise to 5-HT neurons. Here we show in the mouse that Ascl1 is essential for the birth of 5-HT neurons, both as a proneural gene for the production of postmitotic neuronal precursors and as a determinant of the serotonergic phenotype for the parallel activation of Gata3, Lmx1b and Pet1. Thus Ascl1, which is essential for noradrenergic differentiation, is also a determinant of the serotonergic phenotype.

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Acknowledgements

We thank D. Engel, J. Ericson, R. Kageyama, J. Nardelli, O. Pabst, C. Ragsdale and J. Rubenstein for antibodies and probes. This work was supported by the Centre National de la Recherche Scientifique and grants from the European Community (QLG2-CT-2001-01467), Association pour la Recherche sur le Cancer (ARC) and Association Française contre les Myopathies (AFM).

Author information

Author notes

    • J Hikke van Doorninck

    Present address: Department of Neurosciences, Erasmus MC, Box 1738, 3000DR Rotterdam, The Netherlands.

Affiliations

  1. CNRS UMR 8542, Ecole Normale Supérieure, 75005 Paris, France.

    • Alexandre Pattyn
    • , Christo Goridis
    •  & Jean-François Brunet
  2. Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.

    • Nicolas Simplicio
    •  & François Guillemot
  3. Department of Cell Biology, Erasmus MC, Box 1738, 3000DR Rotterdam, The Netherlands.

    • J Hikke van Doorninck

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jean-François Brunet.

Supplementary information

Image files

  1. 1.

    Supplementary Fig. 1

    In situ hybridizations showing that genes encoding neurogenins are not expressed in pMNv and are not upregulated in Ascl1 mutants.

  2. 2.

    Supplementary Fig. 2

    Schematic of pan-neuronal and type-specific transcriptional cascades in pMNv and its progeny from E9.5 to E12 (see text for details). The upregulation of Ascl1 by Phox2b and its intrinsic proneural function (dashed arrows), unmasked by loss-of-function26 and gain-of-function44 experiments are of uncertain functional relevance between E9 and E10.5. The involvement and hierarchical position of Gata2 (italics) during 5-HT neuron production are hypothetical.44. Dubreuil, V. et al. The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis. Development 129, 5241-5253 (2002).

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DOI

https://doi.org/10.1038/nn1247

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