In mammals, the Low Density Lipoprotein Receptor (LDLRs) family comprises nine members structurally and functionally related. The LDLR is the founding member of the family. It is mainly expressed in the liver where it mediates the endocytosis of cholesterol rich LDL particles. Thus, the LDLR is essential for the regulation of systemic cholesterol levels and patients with a defective LDLR suffer from hypercholesterolemia and early heart attacks. Similarly to the LDLR, the main activity of the other eight related proteins is also to mediate the endocytosis of multiple ligands, including lipoproteins, proteases, protease-protease inhibitor complexes, vitamins and their carriers, toxins like Pseudomonas exotoxin A, Amiloid Precursor Protein etc. However, besides this role in endocytosis, we currently know that several LDLRs are also essential for intercellular signaling. Two examples are ApoER2 and VLDLR which are redundant receptors for the extracellular protein Reelin, a signaling molecule required during neuronal migration in the cortex, and LRP5/6 (Arrow in Drosophila) which are essential for Wnt signal transduction.

 

In our lab, we use Drosophila melanogaster as a model organism to study LDLRs and their role in signal transduction and development. We decided to use Drosophila for several reasons: First, the LDLR family is highly evolutionarily conserved, with members in all metazoans examined. Secondly, most signaling pathways had been exhaustively dissected in Drosophila and finally, the fly is highly amenable to genetic and developmental techniques.

In particular, our current research focuses on: (1) Role of LpR1 and LpR2 in lipid metabolism. (2) Modulation of BMP signaling by LRP1 and (3) Megalin´s role in controlling extracellular matrix composition.