Characterization of SHOX functions in bone formation: Identification of target genes and interacting proteins

• Applicant: Professorin Dr. Gudrun Rappold
• Subject Area: Human Genetics
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 30613590

Growth is a complex process that is influenced by a variety of different environmental and genetic factors. Among the genetic factors, an important role of growth and bone development can be attributed to the transcription factor SHOX. SHOX mutations underlie the short stature and the skeletal abnormalities associated with Leri-Weill, Langer and Turner Syndromes. Mutations within the SHOX gene have also been identified in approximately 3 - 5 % of short individuals previously described as idiopathic. Recently we have found that ectopic SHOX expression in osteosarcoma cells and primary chondrocytes leads to cell cycle arrest and apoptosis. We have also shown that endogenous SHOX is expressed in growth plate chondrocytes. Together, these results suggest that SHOX is involved in chondrocyte differentiation but the exact role of SHOX in chondrogenesis has not been elucidated yet. The goat of our proposed project is to characterize the role of SHOX in bone formation and to identify the genes that represent the regulators as well as the downstream target genes instructing bone cell and cartilage differentiation. To accomplish our aim we will focus on two different approaches: Identification of SHOX target genes. We will employ our recently developed in vivo system which is based on the specific differentiation of mesenchymal stem cells into chondrocytes. Previous results using this system suggest that SHOX induction coincides with the chondrocytic differentiation of these cells. The specific activation of the SHOX gene at a certain stage of chondrocyte differentiation provides the opportunity of using this model for gene expression studies aimed at identifying SHOX target genes. Identification of SHOX interacting proteins. We will perform a yeast two hybrid screen of a self-made primary chondrocyte cDNA library using full length SHOX as a bait. The understanding of SHOX functions in bone formation through the identification of SHOX partners and target genes will provide new insights on the processes which take place during bone development.

• DFG Programme: Research Grants