Lipoprotein Receptors Signaling Functions in the Brain?

brain has a characteristic architecture of packed layers of cells with specific functional identities. In VLDLR Ϫ apoER2 Ϫ , reln Ϫ , and dab1 Ϫ brains, these layers are disorganized. For example, the Purkinje cells of the cerebellum normally migrate outward from an origin near the fourth While some nutrients enter cells through transporters, ventricle, to form a thin layer beneath cerebellar granule others, including iron and cholesterol, are actively im-cell precursors. In the mutants, the Purkinje cells initiate ported into cells by specialized receptors. These import migration but remain clustered deeper in the cerebellar receptors continuously recycle between the cell surface primordium (Lambert de Rouvroit and Goffinet, 1998; and intracellular vesicles. Cargo is carried from the cell Trommsdorff et al., 1999). Since the proliferation of gran-surface via clathrin-coated pits to endosomes, acidified ule cells requires mitogens, such as Sonic hedgehog, compartments where the cargo is released. The recep-made by the Purkinje cells, the number of granule cells tors then return to the cell surface for another cycle of is markedly reduced in the mutants, and the mutant import. One import receptor, the low density lipoprotein cerebella are about five times smaller than usual. receptor (LDLR), has been intensively studied because The development of the cortex is orchestrated differ-its malfunction is a cause of atherosclerosis. The LDLR ently (Pearlman et al., 1998). Early neurons form two is essential to transport LDL (complexes of cholesterol, layers, an inner subplate and an outer layer of Cajal-triglycerides, and specific apolipoproteins) out of the Retzius (CR) neurons. Later neurons, which will form the plasma, as first shown by the hallmark analysis of familial cortical plate of the embryonic cortex, move through hypercholesterolemia by Brown and Goldstein. In sub-the subplate layer and come to rest below the CR cells. sequent years, other import receptors related to the As each subsequent cortical plate neuron migrates, it LDLR have been discovered, and the LDLR superfamily bypasses its predecessors, coming to rest immediately now includes at least five mammalian and several inver-below the CR neurons. In the mutants, the migrating tebrate proteins. It has become clear that most of the cells neither penetrate between subplate neurons nor new members of the family do not have a primary func-overtake their brethren (Pearlman et al., 1998; Rice et tion in LDL import, and instead bind and import multiple al., 1998). The CR, subplate, and early cortical plate ligands (see …