title: Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb.
abstract: GDF11, a new member of the TGF-beta gene superfamily, regulates anterior/posterior patterning in the   axial skeleton during mouse embryogenesis. Gdf11 null mice display skeletal abnormalities that appear   to represent anterior homeotic transformations of vertebrae consistent with high levels of Gdf11   expression in the primitive streak, presomitic mesoderm, and tail bud. However, despite strong Gdf11   expression in the limb throughout development, this structure does not appear to be affected in the   knockout mice. In order to understand this dichotomy of Gdf11 expression versus Gdf11 function, we   identified the chicken Gdf11 gene and studied its role during limb formation. In the early limb bud,   Gdf11 transcripts are detected in the subectodermal mesoderm at the distal tip, in a region overlapping   the progress zone. At these stages, Gdf11 is excluded from the central core mesenchyme where   precartilaginous condensations will form. Later in development, Gdf11 continues to be expressed in the   distal most mesenchyme and can also be detected more proximally, in between the forming skeletal   elements. When beads incubated in GDF11 protein were implanted into the early wing bud, GDF11   caused severe truncations of the limb that affected both the cartilage elements and the muscle. Limb   shortening appeared to be the result of an inhibition of chondrogenesis and myogenesis and using an   in vitro micromass assay, we confirmed the negative effects of GDF11 on both myogenic and   chondrogenic cell differentiation. Analysis of molecular markers of skeletal patterning revealed that   GDF11 induced ectopic expression of Hoxd-11 and Hoxd-13, but not of Hoxa-11, Hoxa-13, or the Msx   genes. These data suggest that GDF11 may be involved in controlling the late distal expression of the   Hoxd genes during limb development and that misregulation of these Hox genes by excess GDF11   may cause some of the observed alterations in skeletal element shape. In addition, GDF11 induced the   expression of its own antagonist follistatin, indicating that the activity of GFD11 may be limited by a   negative feedback mechanism. The data from our studies in the chick suggest that Gdf11 plays a role   in the formation and development of the avian limb skeleton.
authors.affiliation: Department of Musculoskeletal Sciences, Genetics Institute, Cambridge, Massachusetts 02140, USA. lgamer@genetics.com
authors.forename: L W
authors.initials: LW
authors.lastname: Gamer
authors.forename: K A
authors.initials: KA
authors.lastname: Cox
authors.forename: C
authors.initials: C
authors.lastname: Small
authors.forename: V
authors.initials: V
authors.lastname: Rosen
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002358:Cartilage, Articular / Q000166:cytology / Q000196:embryology*; D002642:Chick Embryo / Q000502:physiology*; D003001:Cloning, Molecular; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D005809:Genes, Regulator; D055412:Growth Differentiation Factors; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D018878:Limb Buds / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009924:Organ Culture Techniques; D010012:Osteogenesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors; D014921:Wings, Animal / Q000196:embryology
chemical_list: D019485:Bone Morphogenetic Proteins; C492266:GDF11 protein, human; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors