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Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain

Nature Neuroscience volume 6, pages 453–460 (2003)Cite this article

Abstract

Organizing centers emit signaling molecules that specify different neuronal cell types at precise positions along the anterior–posterior (A–P) and dorsal–ventral (D–V) axes of neural tube during development. Here we report that reduction in Otx proteins near the alar–basal plate boundary (ABB) of murine midbrain resulted in a dorsal shift of Shh expression, and reduction in Otx proteins at the midbrain–hindbrain boundary (MHB) resulted in an anterior expansion of the Fgf8 domain. Our data thus indicate that an Otx dose-dependent repressive effect coordinates proper positioning of Shh and Fgf8 expression. Furthermore, this control is effective for conferring proper cell identity in the floor-plate region of midbrain and does not require an Otx2-specific property. We propose that this mechanism may provide both A–P and D–V positional information to neuronal precursors located within the midbrain.

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Figure 1: Generation of the Otx2flox and Otx1cre alleles, comparison between Otx1cre and Otx2 expression and Otx1-driven Cre activity in the R26R genetic background.
Figure 2: Otx1-Cre inactivation of the Otx2flox allele.
Figure 3: Anatomical and histological abnormalities and Otx2 distribution in double heterozygous and conditional mutants.
Figure 4: Abnormal gene expression in the midbrain at E10.5.
Figure 5: Abnormal gene expression in the midbrain at E12.5.
Figure 6: Abnormal differentiation and proliferation in the floor plate region.
Figure 7: Foxa2 and Shh expression is antagonized by Otx genes at the ABB.

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Acknowledgements

We thank A. Lumsden, A. Pierani, L. Puelles and C. Stern for comments on the manuscript. We are grateful to J. Rubenstein for the Nkx6-1 probe, A. Pierani for Msx1 and Dbx1 probes, G. Cossu for the R26R mouse strain, S. Guthrie for αISL1 and A. Secondulfo and S. Boscolo for manuscript preparation. We are also indebted to L. Cashnella and J. Marven for excellent animal care. This work was supported by the Medical Research Council (N. G9900955), the Wellcome Trust (N. 062642/Z/00), the EU BIOTECH Program (N.QLG3-CT-2000-02310), the FIRB Neuroscienze PNR 2001–2003 (FIRB art.8) D.M. 199, the MURST-CNR Program “legge 488/92” (cluster 02) and the Fondation Bettencourt-Schueller to A.S. This work was also supported by the EU BIOTECH Programme, the Association pour la Recherche sur le Cancer, the Institute National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique and the Hôpital Universitaire de Strasbourg to S.L.A., and by the Bundesministerium für Bildung und Forschung (BMBF) to W.W. E.L. was supported by a pre-doctoral fellowship from the Ministère de la Recherche, and S.F. was supported by an EMBO fellowship.

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Author notes

  1. Eduardo Puelles, Dario Acampora and Emmanuel Lacroix: These first three authors contributed equally to this work

Authors and Affiliations

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

    Eduardo Puelles, Dario Acampora, Massimo Signore, Alessandro Annino & Antonio Simeone

  2. Institute of Genetics and Biophysics, A. Buzzati-Traverso, CNR, Via G. Marconi 12, Naples, 80125, Italy

    Dario Acampora, Francesca Tuorto, Stefania Filosa & Antonio Simeone

  3. IGBMC, 1 rue Laurent Fries, BP163, CU de Strasbourg, 67404, Illkirch cedex, France

    Emmanuel Lacroix, Stefania Filosa & Siew-Lan Ang

  4. IST National Institute for Cancer Research, Universita' di Genova, Largo Benzi, Genova, 16132, Italy

    Giorgio Corte

  5. Dipartimento di Oncologia Clinica e Sperimentale, Universita' di Genova, Largo Benzi, Genova, 16132, Italy

    Giorgio Corte

  6. GSF Research Center, Institute of Developmental Genetics, 85764 Munich/Neuherberg, Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Kraepelinstr. 2-16, Munich, 80804, Germany

    Wolfgang Wurst

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Puelles, E., Acampora, D., Lacroix, E. et al. Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci 6, 453–460 (2003). https://doi.org/10.1038/nn1037

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