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Analysis of the Transcriptional Network that Controls Skeletal Development and Regeneration

Prof. Mundlos (first supervisor), Prof. Knaus (second supervisor), Dr. Hecht (mentor);
Max Planck Institute for Molecular Genetics and Freie Universität Berlin

Knowing the signalling cascades and transcriptional networks that control skeletal development and regeneration is of great importance for influencing, accelerating or modifying bone healing and homeostasis. Based on the hypothesis that regeneration recapitulates development not only on morphological but also on molecular basis, we are using developmental models of cell and tissue differentiation to identify genes involved in bone regeneration and development. This will enhance the molecular basis for improved therapeutic approaches for treatment of fractures and skeletal diseases like osteoporosis.
The aim of the proposed project is to identify target genes and the regulatory interplay of different transcription factors with a role in skeletogenesis, e.g. Runx2. Heterozygous mutations in Runx2 cause Cleidocranial Dysplasia (CCD), a condition characterized by clavicular hypoplasia, patent fontanels, short stature, and osteopenia. While heterozygous Runx2 deficient mice resemble the human CCD phenotype, the complete inactivation of Runx2 leads to a lack of bone due to a defect in osteoblast and chondrocyte differentiation.
State-of-the-art techniques like chromatin immunoprecipitation and subsequent analysis of target sequences by massively parallel sequencing (ChIPSeq) will be used to unravel the complex transcriptional process that controls differentiation from mesenchymal precursor cells to differentiated cells of cartilage and bone. Validation and functional characterization of candidate genes will be performed using a broad spectrum of biochemical, molecular biological, and genetic methods in in vitro and in vivo model systems.

References
Hecht J, Seitz V, Urban M, Wagner F, Robinson PN, Stiege A, Dieterich C, Kornak U, Wilkening U, Brieske N, Zwingman C, Kidess A, Stricker S, Mundlos S. Detection of novel skeletogenesis target genes by comprehensive analysis of a Runx2(-/-) mouse model. Gene Expr. Patterns. 2007;7(1-2):102-12.

Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997;89(5):773-9.

Hecht J, Kuhl H, Haas SA, Bauer S, Poustka AJ, Lienau J, Schell H, Stiege AC, Seitz V, Reinhardt R, Duda GN, Mundlos S, Robinson PN. Gene identification and analysis of transcripts differentially regulated in fracture healing by EST sequencing in the domestic sheep. BMC Genomics. 2006;7:172.