BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development

Maxence Vieux-Rochas, Kamal Bouhali, Stefano Mantero, Giulia Garaffo, Paolo Provero, Simonetta Astigiano, Ottavia Barbieri, Mariano F. Caratozzolo, Apollonia Tullo, Luisa Guerrini, Yvan Lallemand, Benoît Robert, Giovanni Levi, Giorgio R. Merlo

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Article numbere51700
JournalPLoS One
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 29 2013

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limbs (animal)
Extremities
Genes
Defects
Molecules
Bioinformatics
Mesoderm
mutants
Transcription Factors
Derivatives
mice
Hindlimb
Computational Biology
bioinformatics
etiology
mechanism of action
genes
transcription factors
chemical derivatives
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Vieux-Rochas, M., Bouhali, K., Mantero, S., Garaffo, G., Provero, P., Astigiano, S., ... Merlo, G. R. (2013). BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development. PLoS One, 8(1), [e51700]. https://doi.org/10.1371/journal.pone.0051700

BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development. / Vieux-Rochas, Maxence; Bouhali, Kamal; Mantero, Stefano; Garaffo, Giulia; Provero, Paolo; Astigiano, Simonetta; Barbieri, Ottavia; Caratozzolo, Mariano F.; Tullo, Apollonia; Guerrini, Luisa; Lallemand, Yvan; Robert, Benoît; Levi, Giovanni; Merlo, Giorgio R.

In: PLoS One, Vol. 8, No. 1, e51700, 29.01.2013.

Research output: Contribution to journalArticle

Vieux-Rochas, M, Bouhali, K, Mantero, S, Garaffo, G, Provero, P, Astigiano, S, Barbieri, O, Caratozzolo, MF, Tullo, A, Guerrini, L, Lallemand, Y, Robert, B, Levi, G & Merlo, GR 2013, 'BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development', PLoS One, vol. 8, no. 1, e51700. https://doi.org/10.1371/journal.pone.0051700
Vieux-Rochas, Maxence ; Bouhali, Kamal ; Mantero, Stefano ; Garaffo, Giulia ; Provero, Paolo ; Astigiano, Simonetta ; Barbieri, Ottavia ; Caratozzolo, Mariano F. ; Tullo, Apollonia ; Guerrini, Luisa ; Lallemand, Yvan ; Robert, Benoît ; Levi, Giovanni ; Merlo, Giorgio R. / BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development. In: PLoS One. 2013 ; Vol. 8, No. 1.
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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.",
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