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  Director : ROBERT, Benoît (brobert@pasteur.fr)



Our laboratory is involved in the study of embryonic induction in vertebrate development. The main emphasis is on the role of Msx1 and Msx2 in signal transduction associated to several signalling pathways (BMP, WNT...). These two homeobox genes are prominently expressed in sites of induction and our approach relies on mouse mutants we have produced for both genes. We also analyse the relationship between expression of these genes and cell plasticity, in the prospect of isolating pluripotent somatic stem cells.



The Morphogenesis molecular Genetics Laboratory is involved in the study of ecto-mesodermal induction mechanisms that are implicated in organogenesis, with special emphasis on limb initiation and morphogenesis and on formation of the dorsal midline of the neural tube, in vertebrates. This work relies primarily on the analysis of mice mutant for Msx1 or Msx2 that we produced by homologous recombination.

Function of Msx genes in limb morphogenesis (Yvan Lallemand, Mathilde Maufras, Marie-Anne Nicola).

Msx1 and Msx2 are homeobox genes prominently expressed in regions of induction between ectoderm and mesoderm. Both genes have been inactivated by insertion of an nLacZ reporter gene in the coding sequence, which further permits to monitor gene expression. Msx1 mutants exhibit cranio-facial defects at birth in derivatives of the first branchial arches (maxilla, mandible, tooth buds) which lead to perinatal death; Msx2 mutants are viable and fertile, but their hair follicles are abnormal and they loose hair shortly after birth. Neither mutation affects limb formation. However, the double homozygous mutant exhibits oligodactyly and compound mutants, which retain only one functional allele for either gene, polydactyly. These mutants furthermore show a delay in phalanx ossification and in interdigital webbing regression. All these defects may be correlated with alterations in the BMP4 signalling pathway, which is involved in many steps of limb morphogenesis.

Function of Msx genes in the formation of the dorsal midline of the neural tube (Antoine Bach, Yvan Lallemand, Marie-Anne Nicola).

Msx1 and Msx2, as well as Msx3, are also expressed at the dorsal midline of the neural tube. We have observed that Msx1 mutants suffer from hydrocephalus. Histological analysis shows that the subcommissural organ, an ependymal secretory structure located under the posterior commissure of the brain, is absent in the mutant. Further investigations demonstrated that the whole roof of the diencephalon is affected. In the absence of Msx1, several signalling factors normally expressed in the dorsal midline (BMPs, WNTs, ...) are missing, which leads to the downregulation of genes expressed laterally. Thus, Msx1 seems to be required for the function of the dorsal midline as a signalling centre. Analysis of the early phenotype and of Msx1/Msx2 double mutants shows that these genes are required for the expression of Wnt1, which plays an essential role in cellular proliferation in the dorsal neural tube. Our observations indicate that at this site, Msx genes may be involved in signal transduction between the ectoderm and the neuroectoderm.

Expression of Msx genes as a signature of cell plasticity (Marie-Anne Nicola; in collaboration with Didier Montarras, Unité de Génétique moléculaire du Développement).

At induction sites, Msx genes are expressed in mesenchymal cells that proliferate and differentiate into several histological cell types (bone, tendon, dermis...). Furthermore, they are induced in regeneration blastema in urodele amphibians. Recent work has shown that forced expression into differentiated myotubes leads them to fragmentation and re-entry in cell cycle. These cells can then give rise to derivatives from several lineages. These properties suggest that expression of Msx genes may be associated with a state of cell plasticity characteristic of pluripotent stem cells. Taking advantage of the nLacZ reporter in the Msx1 and Msx2 loci, we have observed expression of these genes in scattered cells in adult mice, especially in blood vessels. Vascular cells in culture do proliferate while retaining Msx gene expression and simultaneously express markers from two distinct lineages, endothelium and smooth muscle.

Keywords: Embryonic induction, Msx, limb, neural tube, intercellular signalling, hydrocephalus

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  Office staff Researchers Scientific trainees Other personnel
  Demond, Anne (ademond@ pasteur.fr) Robert, Benoît, Institut Pasteur (brobert@pasteur.fr)

Lallemand, Yvan, Institut Pasteur (yvanlal@pasteur.fr)

Bach, Antoine, PhD student from Paris XI University

Maufras, Mathilde, DEA student from Paris VI University

Nicola, Marie-Anne (Engineer Institut Pasteur,manicola@pasteur.fr)

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