title: Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development.
abstract: The homeobox-containing genes Msx1 and Msx2 are highly expressed in the limb field from the earliest stages of limb formation and, subsequently, in both the apical ectodermal ridge and underlying mesenchyme. However, mice homozygous for a null mutation in either Msx1 or Msx2 do not display abnormalities in limb development. By contrast, Msx1; Msx2 double mutants exhibit a severe limb phenotype. Our analysis indicates that these genes play a role in crucial processes during limb morphogenesis along all three axes. Double mutant limbs are shorter and lack anterior skeletal elements (radius/tibia, thumb/hallux). Gene expression analysis confirms that there is no formation of regions with anterior identity. This correlates with the absence of dorsoventral boundary specification in the anterior ectoderm, which precludes apical ectodermal ridge formation anteriorly. As a result, anterior mesenchyme is not maintained, leading to oligodactyly. Paradoxically, polydactyly is also frequent and appears to be associated with extended Fgf activity in the apical ectodermal ridge, which is maintained up to 14.5 dpc. This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling.
authors.affiliation: Unité de Génétique Moléculaire de la Morphogenèse, Institut Pasteur, URA 2578 du CNRS, 25 rue du Dr Roux, 75724 Paris, Cedex 15, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Lallemand
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Nicola
authors.forename: Casto
authors.initials: C
authors.lastname: Ramos
authors.forename: Antoine
authors.initials: A
authors.lastname: Bach
authors.forename: Cécile Saint
authors.initials: CS
authors.lastname: Cloment
authors.forename: Benoît
authors.initials: B
authors.lastname: Robert
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004475:Ectoderm / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051957:MSX1 Transcription Factor; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse