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Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis

Nature Neuroscience volume 10, pages 1433–1439 (2007)Cite this article

Abstract

In many regions of the developing CNS, distinct cell types are born at different times. The means by which discrete and stereotyped temporal switches in cellular identities are acquired remains poorly understood. To address this, we have examined how visceral motor neurons (VMNs) and serotonergic neurons, two neuronal subtypes, are sequentially generated from a common progenitor pool in the vertebrate hindbrain. We found that the forkhead transcription factor Foxa2, acting in progenitors, is essential for the transition from VMN to serotonergic neurogenesis. Loss-of-function and gain-of-function experiments indicated that Foxa2 activates the switch through a temporal cross-repressive interaction with paired-like homeobox 2b (Phox2b), the VMN progenitor determinant. This mechanism bears a marked resemblance to the cross-repression between neighboring domains of transcription factors that establish discrete progenitor identities along the spatial axes. Moreover, the subsequent differentiation of central serotonergic neurons required both the suppression of VMN neurogenesis and the induction of downstream intrinsic determinants of serotonergic identity by Foxa2.

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Figure 1: Foxa2 expression in p3 progenitors correlates with the spatio-temporal patterns of serotonergic neuronal differentiation.
Figure 2: Temporal cross-repression between Foxa2 and Phox2b.
Figure 3: Foxa2 is required in p3 progenitors for the generation of central serotonergic neurons.
Figure 4: Conditional deletion of Foxa2 using a Nestin-Cre line (Foxa2-Nestin CKO) reduces the number of serotonergic neurons at all axial levels, but does not affect VMNs.

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Acknowledgements

We thank K. Kaestner for conditional Foxa2 mutant mice, J.-F. Brunet and C. Goridis for Phox2b mutant mice, and R. Krumlauf for Hoxb1 mutant mice. J.-F. Brunet, A. Gould, V. Ribes and C. Maurange provided comments on the manuscript. This work was funded by the UK Medical Research Council.

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Authors and Affiliations

  1. Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    John Jacob, Anna L Ferri, Christopher Milton, Fabrice Prin, Wei Lin, Siew-Lan Ang & James Briscoe

  2. National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    John Jacob

  3. Département de Biologie, Centre National de la Recherche Scientifique UMR8542, Ecole Normale Supérieure, 46 Rue d'Ulm, Paris, 75005, France

    Patrick Pla

  4. Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens, 11527, Greece

    Anthony Gavalas

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Contributions

J.J. and J.B. conceived the project, designed the experiments and wrote the manuscript. J.J. and C.M. carried out the experiments. F.P. performed in ovo electroporation of Foxa2, which W.L. cloned. A.L.F., P.P. and A.G. maintained and generated mutant mouse lines. S.-L.A. constructed the conditional Foxa2 mutant line.

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Correspondence to Siew-Lan Ang or James Briscoe.

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Jacob, J., Ferri, A., Milton, C. et al. Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis. Nat Neurosci 10, 1433–1439 (2007). https://doi.org/10.1038/nn1985

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