Mutations in extracellular matrix components underlie various congenital human developmental diseases, such as Fraser syndrome (mutations in Fras1 or Frem2), Marfan syndrome (mutations in Fibrillin-1 / Fbn1). Using forward genetics, we recently identified zebrafish mutants in Fras1, Frem2 and Fibrillin-2 (Fbn2), all of which show similar defects. In addition, we identified several novel genes not analysed in mammals as yet, which give very similar phenotypes, among them the two hemicentin genes hmcn1 and hmcn2, encoding large ECM proteins with unknown function (Carney et al., 2010). In the meantime, applying recombinant gene targeting, we have generated mouse Hmcn1 and Hmcn2 null mutants. Both are viable, but display multiple defects, including reduced locomotion activity.

The suggested project aims to perform an in-depth phenotypic analysis of both single mutants, as well as Hmcn1/Hmcn2 double mutants (including electron microscopy), along with expression analyses of both genes via in situ hybridizations and immunostainings with specific antibodies generated in our laboratory, and in comparison to other ECM components such as Fibrillins. In addition, genetic interactions with mouse Fbn2 mutants will be carried out, which display – at least on the macroscopic level – some similar phenotypic traits. These studies will be complemented with biochemical approaches addressing a possible physical interaction between Hemicentins and Fibrillins, and with functional analyses of the genes in zebrafish.

Finally, the candidate will search for Hmcn mutations in DNA samples of corresponding human patients (in collaboration with Bernd Wollnik, Institute of Human Genetics, Cologne University Hospital). The candidate will be introduced into all of these systems and the corresponding technologies by senior postdocs of the laboratory with long-standing experience in mouse development, biochemistry or zebrafish development.