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First published online March 7, 2005
doi: 10.1242/10.1242/dev.01718

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Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP 10142, 67404 Illkirch Cedex, C.U. de Strasbourg, France
² Unité d'Embryologie Moléculaire, Institut Pasteur, Bat. J. Monod, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
³ E. Kennedy Shriver Center, University of Massachusetts Medical School, University of Massachusetts, Waltham, MA 02452, USA
⁴ Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

^* Authors for correspondence (e-mail: isalr{at}igbmc.u-strasbg.fr and dolle{at}igbmc.u-strasbg.fr)

Accepted 5 January 2005

Retinoic acid (RA) activity plays sequential roles during the development of the ventral spinal cord. Here, we have investigated the functions of local RA synthesis in the process of motoneuron specification and early differentiation using a conditional knockout strategy that ablates the function of the retinaldehyde dehydrogenase 2 (Raldh2) synthesizing enzyme essentially in brachial motoneurons, and later in mesenchymal cells at the base of the forelimb. Mutant (Raldh2^L–/–) embryos display an early embryonic loss of a subset of Lim1+ brachial motoneurons, a mispositioning of Islet1+ neurons and inappropriate axonal projections of one of the nerves innervating extensor limb muscles, which lead to an adult forepaw neuromuscular defect. The molecular basis of the Raldh2^L–/– phenotype relies in part on the deregulation of Hoxc8, which in turn regulates the RA receptor RARß. We further show that Hoxc8 mutant mice, which exhibit a similar congenital forepaw defect, display at embryonic stages molecular defects that phenocopy the Raldh2^L–/– motoneuron abnormalities. Thus, interdependent RA signaling and Hox gene functions are required for the specification of brachial motoneurons in the mouse.

Key words: Motoneurons, Retinoic acid, Spinal cord, Raldh2, Hox genes, Lim1, Islet1, Mouse

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