Morphogenesis Molecular Genetics - URA CNRS 2578  


  HEADDr. ROBERT Benoît / brobert@pasteur.fr
  MEMBERSMs BENSOUSSAN Vardina / M. LOPES Miguel/ Ms BERTHIER Aurore / Dr. DUVAL Nathalie / Dr. GOUPILLE Olivier / Dr. LALLEMAND Yvan


  Annual Report

We are interested in secondary induction and organogenesis in vertebrates. We are focusing on the function of Msxhomeobox genes in these processes, using several mutant alleles for both Msx1 andMsx2 we have generated in the mouse. In addition, we are investigating the function of Msxgenes in the adult mouse vascular smooth muscle.

Msx genes and anterior identity in the limb

In Msx1:Msx2 double null mutants, anterior elements of the limb skeleton (radius, tibia, thumb) fail to form. This is due to impairment in dorso-ventral specification of the ectoderm that precludes apical ectodermal ridge formation anteriorly. UsingMsx1-/-;Msx2+/- compound mutants and a conditional null allele ofMsx2, we further show that inactivating Msx genes in the mesoderm is sufficient to preclude anterior specification. In the limb, antero-posterior polarization depends on theShh / Gli3signalling. Our results demonstrate that genes act downstream of this pathway both to specify anterior identity and to induce apoptosis anteriorly, thus contributing to the thumb specific morphology.

Role of Msx genes in the formation of the dorsal midline (roof plate) of the neural tube

Msx1 and are expressed in the dorsal midline of the neural tube. In the Msx1mutant, the dorsal midline of the diencephalon adopts a more lateral identity, in correlation with epistasis of Msx1overWnt1. We have investigated the effect of theMsx1:Msx2 double mutation in the spinal cord, and show that these genes are involved in dorsal neural tube patterning and dorsal interneuron specification. This contributes to clarify the signalling pathways that preside to tube dorso-ventral patterning.

Role of Msx genes in mural cells of blood vessels

Using nLacZ-expressing alleles, we showed thatMsx1 and are expressed in the smooth muscle layer of peripheral arteries, up to the latest stages of life.Msx2 expression is restricted to the large arterial trunks, whereas Msx1expression is also observed in smaller arteries and capillaries, where it labels a sub-population of pericytes. Pericytes regulate capillary blood flow and have been proposed to constitute a reservoir for muscle progenitor cells. This suggests possible roles forMsx genes in homeostasis and regeneration, which we are currently investigating.

Keywords: embryonic induction, organogenesis, limb bud, central nervous system, intercellular signalling, vascular smooth muscle, stem cell

Gmmorpho.jpg

(upper row, whole mount) Msx2 is expressed prominently in smooth muscle cells of peripheral arteries (A) and veins (V). Msx1 is expressed to a lesser level in these arteries (A), but strongly in smaller vessels (arrowheads) including capillaries where it labels pericytes. (lower row, sections). These are characterized as contractile cells that express NG2 (green) and surround the CD31-positive endothelium (red).



  Publications

Ramos C, Fernández-Llebrez P, Bach A, Robert B, Soriano E. 2004. Msx1 disruption leads to diencephalon defects and hydrocephalus. Dev Dyn 230:446-460.PMID: 15188430

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. PMID: 15930102

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. PMID: 16439212

Robert B, Lallemand Y. 2006. Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics. Dev Dyn 235:2337-2352. PMID: 16894622

Robert B. 2007. Bone morphogenetic protein signaling in limb outgrowth and patterning. Dev Growth Differ 49:455-468. PMID: 17661740



  Web Site

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Activity Reports 2007 - Institut Pasteur
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