PT - JOURNAL ARTICLE AU - Bertrand Vernay AU - Muriel Koch AU - Flora Vaccarino AU - James Briscoe AU - Antonio Simeone AU - Ryoichiro Kageyama AU - Siew-Lan Ang TI - Otx2 Regulates Subtype Specification and Neurogenesis in the Midbrain AID - 10.1523/JNEUROSCI.5158-04.2005 DP - 2005 May 11 TA - The Journal of Neuroscience PG - 4856--4867 VI - 25 IP - 19 4099 - http://www.jneurosci.org/content/25/19/4856.short 4100 - http://www.jneurosci.org/content/25/19/4856.full SO - J. Neurosci.2005 May 11; 25 AB - 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 Otx2flox/flox animals with Nestin-Cre transgenic animals. In Nestin-Cre/+; Otx2flox/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/+; Otx2flox/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.