The role of fibulin-4 in development and homeostasis of elastic components of the skeletal connective tissue

• Antragsteller: Professor Klaus von der Mark, Ph.D., seit 2/2012
• Fachliche Zuordnung: Allgemeine Genetik und funktionelle Genomforschung
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 188992290

Fibulin-4 is a 50 kDa extracellular matrix protein belonging to the fibulin protein family. A recent gene targeting study has revealed fibulin-4 to be an essential molecule for the elastic fiber assembly during embryonic development. Mice deficient in fibulin-4 are perinatally lethal due to cardiovascular and lung abnormalities. Our preliminary data revealed that fibulin-4 deficiency in mice also results in skeletal abnormalities. Accordingly, a patient with a recessive missense mutation in fibulin-4 displays not only defects in elastogenesis, but also multiple bone fractures at birth, while two patients showed arachnodactyly. The goal of this project is to clarify the role of fibulin-4 in skeletal development, in particular in the assembly of extracellular matrix components of the skeleton. To this aim, I will analyze the skeletal phenotype of fibulin-4 deficient mouse embryos using morphological, immunohistochemical and in situ hybridization techniques. For the analysis of postnatal tissues, I will generate conditional Fbln4 null mice by crossing with Cola1- Cre deleter mice. Potential impairment of cell differentiation, alterations of matrix assembly, and dysregulation of TGF-β/BMP signaling will be assessed in vitro using primary cells isolated from wild type and fibulin-4 deficient mice. Particular attention will be paid to identify further fibulin-4 binding proteins in order to elucidate the mechanisms by which the absence of fibulin-4 leads to abnormalities in mice and human. Furthermore, pathological consequence of missense mutations found in human patients will be analyzed using mutagenized, recombinantly produced fibilin-4 mutants in vitro. The proposed studies will provide novel insights into the role of fibulin-4 in skeletal system as well as in the development and homeostasis of cardiovascular tissue.

• DFG-Verfahren: Sachbeihilfen
• Ehemalige Antragstellerin: Dr. Takako Sasaki, bis 2/2012