title: BMP-mediated functional cooperation between Dlx5;Dlx6 and Msx1;Msx2 during mammalian limb development.
abstract: The Dlx and Msx homeodomain transcription factors play important roles in the control of limb development. The combined disruption of Msx1 and Msx2, as well as that of Dlx5 and Dlx6, lead to limb patterning defects with anomalies in digit number and shape. Msx1;Msx2 double mutants are characterized by the loss of derivatives of the anterior limb mesoderm which is not observed in either of the simple mutants. Dlx5;Dlx6 double mutants exhibit hindlimb ectrodactyly. While the morphogenetic action of Msx genes seems to involve the BMP molecules, the mode of action of Dlx genes still remains elusive. Here, examining the limb phenotypes of combined Dlx and Msx mutants we reveal a new Dlx-Msx regulatory loop directly involving BMPs. In Msx1;Dlx5;Dlx6 triple mutant mice (TKO), beside the expected ectrodactyly, we also observe the hallmark morphological anomalies of Msx1;Msx2 double mutants suggesting an epistatic role of Dlx5 and Dlx6 over Msx2. In Msx2;Dlx5;Dlx6 TKO mice we only observe an aggravation of the ectrodactyly defect without changes in the number of the individual components of the limb. Using a combination of qPCR, ChIP and bioinformatic analyses, we identify two Dlx/Msx regulatory pathways: 1) in the anterior limb mesoderm a non-cell autonomous Msx-Dlx regulatory loop involves BMP molecules through the AER and 2) in AER cells and, at later stages, in the limb mesoderm the regulation of Msx2 by Dlx5 and Dlx6 occurs also cell autonomously. These data bring new elements to decipher the complex AER-mesoderm dialogue that takes place during limb development and provide clues to understanding the etiology of congenital limb malformations.
authors: Evolution des Régulations Endocriniennes, Centre national de la recherche scientifique, UMR-7221, Muséum National d'Histoire Naturelle, Paris, France.
authors: Maxence
authors: M
authors: Vieux-Rochas
authors: Kamal
authors: K
authors: Bouhali
authors: Stefano
authors: S
authors: Mantero
authors: Giulia
authors: G
authors: Garaffo
authors: Paolo
authors: P
authors: Provero
authors: Simonetta
authors: S
authors: Astigiano
authors: Ottavia
authors: O
authors: Barbieri
authors: Mariano F
authors: MF
authors: Caratozzolo
authors: Apollonia
authors: A
authors: Tullo
authors: Luisa
authors: L
authors: Guerrini
authors: Yvan
authors: Y
authors: Lallemand
authors: Benoît
authors: B
authors: Robert
authors: Giovanni
authors: G
authors: Levi
authors: Giorgio R
authors: GR
authors: Merlo
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004475:Ectoderm / Q000254:growth & development / Q000378:metabolism; D005121:Extremities / Q000254:growth & development*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008648:Mesoderm / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009154:Mutation
chemical_list: D019485:Bone Morphogenetic Proteins; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse
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