title: 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.
abstract: 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 (Raldh2L-/-) 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 Raldh2L-/- phenotype relies in part on the deregulation of Hoxc8, which in turn regulates the RA receptor RARbeta. We further show that Hoxc8 mutant mice, which exhibit a similar congenital forepaw defect, display at embryonic stages molecular defects that phenocopy the Raldh2L-/- motoneuron abnormalities. Thus, interdependent RA signaling and Hox gene functions are required for the specification of brachial motoneurons in the mouse.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP 10142, 67404 Illkirch Cedex, C.U. de Strasbourg, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vermot
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schuhbaur
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Mouellic
authors.forename: Peter
authors.initials: P
authors.lastname: McCaffery
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Garnier
authors.forename: Didier
authors.initials: D
authors.lastname: Hentsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Brûlet
authors.forename: Karen
authors.initials: K
authors.lastname: Niederreither
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Roux
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D013116:Spinal Cord / Q000196:embryology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C080041:Hoxc6 protein, mouse; C489816:Hoxc8 protein, mouse; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D014157:Transcription Factors; C065788:transcription factor PEA3; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse