Msx genes are important apoptosis effectors downstream of the Shh/Gli3 pathway in the limb.
In tetrapods, the anteroposterior (AP) patterning of the limb is under the control of the antagonistic activities of the secreted factor Sonic hedgehog (Shh) and Gli3R, the truncated repressor form of the transcription factor Gli3. In this report, we show that Msx1 and Msx2 are targets and downstream effectors of Gli3R. Consequently, in Shh null mutants, Msx genes are overexpressed and, furthermore, partially responsible for the limb phenotype. This is exemplified by the fact that reducing Msx activity in Shh mutants partially restores a normal limb development. Finally, we show that the main action of the Msx genes, in both normal and Shh(-/-) limb development, is to control cell death in the mesenchyme. We propose that, in the limb, Msx genes act downstream of the Shh/Gli3 pathway by transducing BMP signaling and that, in the absence of Shh signaling, their deregulation contributes to the extensive apoptosis that impairs limb development.
CNRS URA, Institut Pasteur, Paris, France.
Yvan
Y
Lallemand
Vardina
V
Bensoussan
Cécile Saint
CS
Cloment
Benoît
B
Robert
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D005121:Extremities / Q000196:embryology / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000196:embryology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
D019485:Bone Morphogenetic Proteins; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D009419:Nerve Tissue Proteins; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3