Molecular Genetics of Skeletal Morphogenesis

DOI: 10.1007/978-1-4615-5115-7_2

ABSTRACT Our understanding of the molecular mechanisms that control growth, patterning and repair of skeletal tissues has increased
greatly in the past few years. An emerging paradigm is that signals important for embryonic skeletal formation are also utilized
by adult organisms to regulate skeletal homeostasis. Current research has shown that bone morphogenetic proteins (BMPs) play
an important role in these processes. BMPs are widely expressed in developing skeletal structures and mutations in individual
BMP genes block early events in skeletal morphogenesis at specific anatomical sites. Based on available information, it seems
likely that different members of the BMP gene family have evolved to control the formation of distinct sets of skeletal structures.
This chapter will focus on BMPs because of their central role in bone formation. We will describe our current understanding
of osteogenic BMP proteins, the BMP signaling pathway, and also discuss the interactions of BMPs with other developmental
molecules that play important roles in skeletal morphogenesis. We will also speculate about the regulation of BMPs by agents
that are known effectors of bone mass in adults, thus defining a potential role for BMPs in adult skeletal homeostasis.

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    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.
    Developmental Biology 02/2001; 229(2):407-20. · 3.87 Impact Factor