ROLE OF MORPHOGENETIC PROTEINS IN EMBRYOGENESIS AND TISSUE REGENERATION

在过去的一年里，我们已经鉴定了5个与这种疾病相关的基因

During the past year, we have characterized five genes related to the bone morphogenetic protein family of growth factors. These proteins are emerging as key determinants in the specification of positional information during embryogenesis and have assumed importance to the biotechnology community owing to their almost certain therapeutic utility in a variety of clinical contexts, including nonunion fractures and other orthopedic and reconstructive indications, alveolar ridge augmentation, and other types of tissue repair. One of these , Anti-Dorsalizing Morphogenetic Protein (ADMP), exerts profound effects on the anatomic pattern of the entire embryo. Though it is expressed in the embryonic region associated with induction of dorsal and neural structures, it profoundly suppresses them when overexpressed. ADMP is the only such growth factor identified so far. Because its expression is increased in response to manipulations that produce exaggerated dorsal structures, we propose that the protein acts as a feedback system that moderates the effects of naturally occurring dorsalizing signals in vivo. Two members of a distinct subfamily of these growth factors, originally identified in Xenopus genomic DNA and then characterized in collaboration with Dr. Frank Luyten of NIDR, have been implicated in patterning of the developing vertebrate limb by hybridization in situ and genetic studies in mammals. These genes, termed Cartilage-Derived Morphogenetic Proteins (CDMPs) are expressed only in cartilage, and are thus the only growth factors known that are specific for this tissue. We have also isolated a homolog of mammalian Osteogenic Protein-1 (OP-1). This gene demonstrates a complex and dynamic expression pattern (ventral endoderm/mesoderm, eye, ear vesicle, pituitary, pineal, neural axis, and branchial arches, suggesting several distinct roles during embryogenesis. Overexpression of the gene causes induction of ventral markers and pronounced proliferation of ventral tissue. A partial cDNA clone for another novel member of the BMP family has been isolated from Xenopus. This gene is expressed during gastrulation in the animal region of the embryo; its biological activities remain to be identified. Finally, sequence from a novel protein isolated from bovine articular cartilage has been used to isolate the corresponding gene, which demonstrates a complex and dynamic expression pattern in the developing vertebrate limb. Using degenerate PCR, we have identified a homologous gene in Xenopus and are in the process of isolating a complete cDNA clone to enable study of its role in embryonic patterning in tissue repair.