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  Gmmorpho


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


  abstract

 

Our laboratory is involved in the study of embryonic induction in vertebrate development. The function of Msx1 and Msx2, two homeobox genes prominently expressed in sites of induction, is analysed using mouse mutants we have produced for both genes by homologous recombination. The role of these genes in signal transduction in several signalling pathways (BMP, Wnt,...) is under dedicated investigation. We are also analysing the genesis of mouse polydactylies, with special attention to the complex genetic determinism of Pluridigité (Pdt).



  report

cale

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 in vertebrates.

Functional analysis of Msx genes in the mouse (Antoine Bach, Marie-Anne Nicola, Yvan Lallemand). Msx1 and Msx2 are homeobox genes prominently expressed in regions of induction between ectoderm and mesoderm. Msx1 was inactivated a few years ago by insertion of an nLacZ reporter gene in the coding sequence. Mutants exhibit cranio-facial defects at birth in derivatives of the first branchial arches (maxilla, mandible, tooth buds) which lead to perinatal death. We further observed that they suffer from hydrocephaly. This new phenotype appears to be due to a deficiency in the formation of the subcommissural organ, an ependymal secretory structure located under the posterior commissure of the brain. In fact, the whole roof of the diencephalon seems 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 (Pax6). Thus, Msx1 seems to be required for the function of the dorsal midline as a signalling center.

We have achieved the mutation of Msx2 by homologous recombination. The whole coding sequence of the gene was replaced by an nLacZ reporter gene. Using this marker, we are revisiting the expression profile of Msx2 with increased sensitivity and accuracy. We previously characterised expression of Msx1 in progenitor cells of the dermis that migrate out of the somite dermomyotome. We observe a segmental, dorsal expression of Msx2 which partially overlap with that of Msx1. Furthermore, the analysis of Msx1/Msx2 double mutants shows that several sites where the two genes are co-expressed show alterations (central nervous system, limb buds), confirming the functional redundancy between the two genes.

Analysis of mouse polydactylous mutants (Isabelle Blanc, Antoine Bach). We are studying a new mouse polydactyly, Pluridigité (Pdt). The phenotype appears to depend on the interactions between three genes, a major locus on chromosome 12, close to Twist. Allelism tests have confirmed that Twist is the affected gene. In addition, two strong modifier loci on chromosome 4 are required for the expression of the mutation. These genes have been fixed in the proper allelic configuration in a recombinant inbred strain, which constitutes a precious tool to investigate interactions between the three genes.

Identification of an antisense transcript from the Msx1 locus (in collaboration with Ariane Berdal, University of ParisVII) Comparing the production of the MSX1-LacZ fusion protein in our Msx1 mutant mice with the production of the corresponding RNA led us to the detection of an RNA transcribed from the antisense DNA strand in the Msx1 locus. Overexpression of this RNA in a cell culture system leads to a reduction in the level of the MSX1 protein, suggesting that an original regulation system plays a role downstream of transcription to modulate MSX1 production.



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  personnel

  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

Blanc, Isabelle, PhD student from Paris VI University (on leave 18/9/01)

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


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