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First published online July 10, 2009
doi: 10.1242/10.1242/dev.031781

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Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain

Nilima Prakash^1,, Eduardo Puelles², Kristine Freude³, Dietrich Trümbach¹, Daniela Omodei⁴, Michela Di Salvio⁴, Lori Sussel⁵, Johan Ericson⁶, Maike Sander^3,*, Antonio Simeone^4, and Wolfgang Wurst^1,7,

¹ Helmholtz Centre Munich, German Research Centre for Environmental Health (GmbH) and Technical University Munich, Institute of Developmental Genetics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ingolstaedter Landstr. 1, 85764 Munich/Neuherberg, Germany.
² Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, San Juan, 03550 Alicante, Spain.
³ Department of Developmental and Cell Biology, School of Biological Sciences, University of California at Irvine, 4203 McGaugh Hall, Irvine, CA 92697-2300, USA.
⁴ CEINGE Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Naples, and SEMM European School of Molecular Medicine, and Institute of Genetics and Biophysics `ABT', Via Guglielmo Marconi 12, 80125 Naples, Italy.
⁵ Department of Genetics and Development, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA.
⁶ Department of Cell and Molecular Biology (CMB), Karolinska Institute, PO Box 285, 171 77 Stockholm, Sweden.
⁷ Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.

Authors for correspondence (e-mails: nilima.prakash{at}helmholtz-muenchen.de; simeone{at}ceinge.unina.it; wurst{at}helmholtz-muenchen.de)

Accepted 21 May 2009

Little is known about the cues controlling the generation of motoneuron populations in the mammalian ventral midbrain. We show that Otx2 provides the crucial anterior-posterior positional information for the generation of red nucleus neurons in the murine midbrain. Moreover, the homeodomain transcription factor Nkx6-1 controls the proper development of the red nucleus and of the oculomotor and trochlear nucleus neurons. Nkx6-1 is expressed in ventral midbrain progenitors and acts as a fate determinant of the Brn3a⁺ (also known as Pou4f1) red nucleus neurons. These progenitors are partially dorsalized in the absence of Nkx6-1, and a fraction of their postmitotic offspring adopts an alternative cell fate, as revealed by the activation of Dbx1 and Otx2 in these cells. Nkx6-1 is also expressed in postmitotic Isl1⁺ oculomotor and trochlear neurons. Similar to hindbrain visceral (branchio-) motoneurons, Nkx6-1 controls the proper migration and axon outgrowth of these neurons by regulating the expression of at least three axon guidance/neuronal migration molecules. Based on these findings, we provide additional evidence that the developmental mechanism of the oculomotor and trochlear neurons exhibits more similarity with that of special visceral motoneurons than with that controlling the generation of somatic motoneurons located in the murine caudal hindbrain and spinal cord.

Key words: Red nucleus, Oculomotor/trochlear nucleus, Nkx6-1, Nkx6-2, Otx2, Dbx1, Mouse

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