Genetic analysis of latrophilin function in the mouse. (360G-Wellcome-075336_Z_04_B)

WT Studentship - 4 yr PhD The LN7TM family - an usual subclass of G-protein coupled receptor G-protein coupled receptors (GPCR) are key regulators of many biological processes, and the targets for a large number of successful drugs. The investigation of uncharacterized "orphan" GPCR is a promising area for understanding disease biology and a priority for the development of new therapeutics. The LN-7TM receptors are the least well understood family of GPCR, characterized by an unusual domain structure with a long N-terminus (LN) and a secretin-receptor-like seven-transmembrane (7-TM domain. The N-terminus typically contains protein domains found in adhesion molecules. Mammalian genomes encode for around 30 receptors of this type. Very little information is available about ligands, signaling mechanisms and the physiological functions of LN-7TM receptors. Recent reports associate several members of the family with clinically relevant neurological phenotypes. For example, mutations in the human GPR56 gene cause bilateral frontoparietal polymicrogyria, a rare inherited disease with defects in cortical lamination. Latrophilins - highly conserved LN-7TM receptors acting in the nervous system The calcium-independent receptor of latrotoxin (CIRL/Latrophilin, CL), defines a subfamily of LN-7TMs which is very highly conserved in evolution, suggesting that it fulfils a fundamental function conserved across phyla. In mammals there are three unlinked paralogs, CL1-3, while C.elegans encodes two paralogs, lat-1 and lat-2. In contrast, other receptors like GPR56 or the GPR110-116 cluster seem to have evolved more recently and are still rapidly evolving in vertebrates (Russ et al, unpublished). The endogenous ligands and signal transduction pathways of CLs are not known. The project will address the following questions by genetic analysis in the mouse model: Is CL signaling required for the development of the nervous system? Are the functions of the CL paralogs CL1-3 specialize or partly overlapping? Does CL function modulate synaptic signaling?