"From Fly to Fish: how to shape the embryo. Our 25 years long saga"
Part I : Patterning the dorso-ventral axis
Bernard Thisse and Christine Thisse
Starting in the 1980s working on fly, we isolated twist, a gene required for involution of the mesoderm
at gastrula stage and coding for a bHLH transcription factor. We then established that its expression
was directly controled by the maternal protein dorsal showing that the transfert of the maternal
information to the embryo involves a cascade of transcriptional activation. After a switch from fly to
fish organism, we dissected the mechanisms controling the D-V axis formation in vertebrate and
established that the functional morphogene of the D-V axis is an heterodimer between BMP2b and
BMP7 and that the activity of these ventraly secreted morphogenes is regulated by a combination of
dorsaly secreted inhibitors that comprize, in addition to chordin, the noggin1 and follistatin like 2
factors. Moreover, we discover that the mechanisms restricting the transcription of these bone
morphogenetic protein to the ventral side of the embryo is controled by the FGF signaling pathway
acting through the FGFR1, Ras-MAPKinase pathway. More recently we identified transcription
factors from the foxA family as responsible for the formation of the dorsal structures of vertebrate
embryo and we establish that the homeobox transcription factor Lbx1a is required for the patterning of
the D-V axis through a control of the Wnt/ßcatenin signaling pathway at the level of the activity of the
TCF/LEF corepressor groucho.
"From Fly to Fish: how to shape the embryo. Our 25 years long saga"
Part II : Patterning of the antero-posterior axis
Christine Thisse and Bernard Thisse
Amongst the genes expressed in time and place of primary inductions that we isolated during the
course of a high throughput in situ hybridization screen (25,000 genes described so far), we identified
a gene coding for a variant form of TGFbeta named Antivin. This gene is homologous to the mouse
Lefty and functions as a competitive inhibitor of the Activin/Nodal signaling pathway. Using this
factor as a tool to inhibit the function of the Activin/Nodal pathway we established that the embryo is
patterned along the vegetal to animal axis (that will correspond to the antero-posterior axis later in
development) by a gradient of activity of the Nodal pathway. We then performed graft experiments as
well as local stimulation of animal pole cells (considered as a naïve territory) using various
combination of signaling pathways. These experiments allowed us to identify the ventral marginal
domain and triple combination of BMP, Nodal and Wnt8 to be responsible for the organisation of the
caudal part of the embryo. On the other hand, inactivation of these 3 signaling pathways, and in
particular dorsal inactivation of the Wnt8 signal is required to allow the development of the anterior
most part of the embryo. This was established through knock-down of two transcription factors,
goosecoid and FoxA3 that function as transcriptional repressors and whose activity is required to
restrict the transcription of the zygotic Wnt8 expression to ventral and lateral margin of the embryo.
Further dissection of the organizing activities of the embryo revealed that the organisation of the
embryo is not under the control of single or discrete organizing centers (like dorsal, ventral or lateral
organizers) but depends of the existence of a continuous and global organizing activity of the blastulagastrula margin. Finally, we demonstrate that this is the interplay between BMP, Wnt8 and Nodal
signaling pathways that leads cells to adopt a particular fate. Most importantly, we found that this is
the ratio between these signals that defines which structures will be made in response to the activity of
the organizing field established at the blastula/gastrula margin.