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.
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.
Vermot
Julien
J
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP 10142, 67404 Illkirch Cedex, C.U. de Strasbourg, France.
Schuhbaur
Brigitte
B
Le Mouellic
Hervé
H
McCaffery
Peter
P
Garnier
Jean-Marie
JM
Hentsch
Didier
D
Brûlet
Philippe
P
Niederreither
Karen
K
Chambon
Pierre
P
Dollé
Pascal
P
Le Roux
Isabelle
I
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
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