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The Journal of Neuroscience, May 15, 2003, 23(10):4199-4207

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Location and Size of Dopaminergic and Serotonergic Cell Populations Are Controlled by the Position of the Midbrain–Hindbrain Organizer

Claude Brodski,^1 * Daniela M. Vogt Weisenhorn,^1 * Massimo Signore,^2 * Inge Sillaber,¹ Matthias Oesterheld,¹ Vania Broccoli,³ Dario Acampora,² Antonio Simeone,² and Wolfgang Wurst¹

¹Max-Planck-Institute of Psychiatry, 80804 Munich, Germany, and GSF-National Research Center for Environment and Health, Technical University Munich, Institute of Developmental Genetics, 85758 Oberschleissheim, Germany, ²Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 UL, United Kingdom, and Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80125 Naples, Italy, and ³Stem Cell Research Institute, Department of Biological and Technological Research–San Raffaele Hospital, I-20132 Milan, Italy

Midbrain dopaminergic and hindbrain serotonergic neurons play an important role in the modulation of behavior and are involved in a series of neuropsychiatric disorders. Despite the importance of these cells, little is known about the molecular mechanisms governing their development. During embryogenesis, midbrain dopaminergic neurons are specified rostral to the midbrain–hindbrain organizer (MHO), and hindbrain serotonergic neurons are specified caudal to it. We report that in transgenic mice in which Otx2 and accordingly the MHO are shifted caudally, the midbrain dopaminergic neuronal population expands to the ectopically positioned MHO and is enlarged. Complementary, the extension of the hindbrain serotonergic cell group is decreased. These changes are preserved in adulthood, and the additional, ectopic dopaminergic neurons project to the striatum, which is a proper dopaminergic target area. In addition, in mutants in which Otx2 and the MHO are shifted rostrally, dopaminergic and serotonergic neurons are relocated at the newly positioned MHO. However, in these mice, the size ratio between these two cell populations is changed in favor of the serotonergic cell population. To investigate whether the position of the MHO during embryogenesis is also of functional relevance for adult behavior, we tested mice with a caudally shifted MHO and report that these mutants show a higher locomotor activity. Together, we provide evidence that the position of the MHO determines the location and size of midbrain dopaminergic and hindbrain serotonergic cell populations in vivo. In addition, our data suggest that the position of the MHO during embryogenesis can modulate adult locomotor activity.

Key words: development; substantia nigra; ventral tegmental area; raphe nuclei; isthmic organizer; hyperactivity

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Received Aug. 8, 2002; revised Feb. 12, 2003; accepted Feb. 18, 2003.

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