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The Journal of Neuroscience, May 11, 2005, 25(19):4856-4867; doi:10.1523/JNEUROSCI.5158-04.2005

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Development/Plasticity/Repair
Otx2 Regulates Subtype Specification and Neurogenesis in the Midbrain

Bertrand Vernay,^1,2 Muriel Koch,^1,2 Flora Vaccarino,³ James Briscoe,² Antonio Simeone,^4,5,6 Ryoichiro Kageyama,⁷ and Siew-Lan Ang^1,2

¹Institut de Génétique et de Biologie Moléculaire et Cellulaire/Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch cedex, Strasbourg, France, ²Division of Developmental Neurobiology, National Institute for Medical Research, London NW7 1AA, United Kingdom, ³Child Study Center, Yale University, New Haven, Connecticut 06520, ⁴Medical Research Council Centre for Developmental Neurobiology, Kings College, London SE1 1UL, United Kingdom, ⁵Institute of Genetics and Biophysics "A. Buzzati-Traverso", Consiglio Nazionale delle Ricerche, 80125 Naples, Italy, ⁶Ceinge Biotecnologie Avanzate, 80131 Naples, Italy, and ⁷Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

The transcription factor Otx2 is required to determine mesencephalic versus metencephalic (cerebellum/pons) territory during embryogenesis. This function of Otx2 primarily involves positioning and maintaining the mid-hindbrain organizer at the border between midbrain and anterior hindbrain. Otx2 expression is maintained long after this organizer is established. We therefore generated conditional mutants of Otx2 using the Cre/loxP system to study later roles during rostral brain development. For inactivation of Otx2 in neuronal progenitor cells, we crossed Otx2^flox/flox animals with Nestin-Cre transgenic animals. In Nestin-Cre/+; Otx2^flox/flox embryos, Otx2 activity was lost from the ventral midbrain starting at embryonic day 10.5 (E10.5). In these mutant embryos, the mid-hindbrain organizer was properly positioned at E12.5, although Otx2 is absent from the midbrain. Hence, the Nestin-Cre/+; Otx2^flox/flox animals represent a novel mouse model for studying the role of Otx2 in the midbrain, independently of abnormal development of the mid-hindbrain organizer.

Our data demonstrate that Otx2 controls the development of several neuronal populations in the midbrain by regulating progenitor identity and neurogenesis. Dorsal midbrain progenitors ectopically expressed Math1 and generate an ectopic cerebellar-like structure. Similarly, Nkx2.2 ectopic expression ventrally into tegmentum progenitors is responsible for the formation of serotonergic neurons and hypoplasia of the red nucleus in the midbrain. In addition, we discovered a novel role for Otx2 in regulating neurogenesis of dopaminergic neurons. Altogether, these results demonstrate that Otx2 is required from E10.5 onward to regulate neuronal subtype identity and neurogenesis in the midbrain.

Key words: Otx2; midbrain; cerebellum; neuronal identity; dopaminergic neurons; serotonergic neurons; conditional inactivation

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Received Dec 17, 2004; revised March 12, 2005; accepted March 13, 2005.

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