|Morphogenesis Molecular Genetics - URA CNRS 2578|
|HEAD||ROBERT, Benoît, Dr. / Benoit.firstname.lastname@example.org|
|MEMBERS||Robert, Benoît, Dr, Chef de Laboratoire, Institut Pasteur / Lallemand, Yvan, Dr, Chargé de Recherche, Institut Pasteur / Nathalie Duval, Dr, Chargée de Recherche, Institut Pasteur
Goupille, Olivier, Dr, Stagiaire Postdoctorant / Bensoussan, Vardina, Etudiante en thèse, Paris V / Miguel Lopes, Etudiant en thèse, Paris VI
Saint Cloment, Cécile, Technicienne Supérieure, Institut Pasteur / Croullebois, Elisabeth, Secrétaire 1er degré / Cretenet, Claudine, Agent de Laboratoire
Berthier, Aurore, Technicienne Supérieure de Laboratoire en apprentissage
We are focusing on three themes linked by the involvement of Msx homeobox genes. We have generated several mutant alleles for both Msx1 and Msx2 in the mouse, which constitute very efficient tools to study gene interactions and function.
Msx genes and morphogenesis of the limb
In Msx1:Msx2 double null mutants, anterior elements of the limb skeleton (radius, tibia, thumb) fail to form. In Msx1-/-;Msx2+/- compound mutants, all digits form but no one shows the characteristic morphology of digit 1, the thumb. Correlatively, the anterior apoptosis domain in the mesenchyme is missing.
In the limb, antero-posterior polarization depends on the Shh / Gli3 signalling. We have demonstrated that Msx genes are downstream targets of Gli3 anteriorly. Furthermore, Msx and Gli3R synergize to induce apoptosis in the anterior limb mesenchyme. We have thus defined a link between patterning that leads to positioning Shh signalling centre, and morphogenesis that locally affects cellular functions such as apoptosis.
Role of Msx genes in the formation of the dorsal midline (roof plate) of the neural tube
Msx1 and Msx2 are expressed in the dorsal midline of the neural tube. In the Msx1:Msx2 double mutant, the dorsal midline is not maintained over the diencephalon and the mesencephalon. In contrast, in the spinal cord, the roof plate is maintained, but is abnormal. In the absence of all Msx function, the progenitors of the dorsalmost interneurons are missing, and the whole dorsal region of the spinal cord is reorganised. This shows that Msx genes play a critical role in the transduction of signals from the roof plate.
Role of Msx genes in mural cells of blood vessels
Using nLacZ-expressing alleles, we showed that Msx1 and Msx2 are expressed in the smooth muscle layer of peripheral arteries, up to the latest stages of life. Msx1 expression further expands to a sub-population of pericytes in the capillaries, where it concentrates at vessel branching points. This suggests that Msx genes may be involved in the restriction of vessel branching. We are further investigating Msx gene function in neo-angiogenesis that accompanies tumour formation. Pericytes have been proposed to constitute a reservoir for muscle progenitor cells. We are exploring this aspect by cell lineage tracing using an Msx1Cre-inducible allele we have recently produced.
Keywords: embryonic induction, organogenesis, limb bud, central nervous system, intercellular signalling, vascular smooth muscle, stem cell
Goupille, O, Saint Cloment, C, Lopes, M, Montarras, D, Robert, B. 2008. Msx1 and Msx2 are expressed in sub-populations of vascular smooth muscle cells. Developmental Dynamics 237:2187-2194.
Robert, B. 2007. Bone morphogenetic protein signaling in limb outgrowth and patterning. Dev Growth Differ 49:455-468.
Robert, B, Lallemand, Y. 2006. Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics. Dev Dyn 235:2337-2352.
Andersson, E, Tryggvason, U, Deng, Q, Friling, S, Alekseenko, Z, Robert, B, Perlmann, T, Ericson, J. 2006. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124:393-405.
Lallemand, Y, Nicola, M-A, Ramos, C, Bach, A, Saint Cloment, C, Robert, B. 2005. Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development. Development 132:3003-3014.
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