The orphan receptor GPR37l1 and the role of primary cilium during postnatal cerebellum development

The mammalian GPR37L1 gene encodes an orphan G-protein coupled receptor that is specifically expressed in newborn and adult cerebellar Bergmann glia astrocytes. It is significantly homologous to the receptors for endothelin and bombesin peptides and its closest homolog GPR37/Pael-R is involved in the pathophysiology of Parkinson's disease. During postnatal cerebellar development GPR37L1 participates in the regulation of granule neuron proliferation/differentiation, Bergmann glia and Purkinje neuron maturation. Furthermore it is involved in Shh-Smo mitogenic signaling and it interacts with the Ptch1 transporter-like component of the Shh receptor complex. Ptch1 and associated components of the Shh-Smo mitogenic pathway are distinctly organized in specialized primary cilia of pre- and postnatal cerebellar astrocytes and neurons. Intriguingly, Gpr37l1 has been identified as a modulator of brain primary ciliogenesis and we postulate that Gpr37l1 may in fact take a key part in the regulation of Shh-Smo signals in the cilium, through its specific interaction with Ptch1. In order to test our hypothesis we are characterising Gpr37l1 localization, subcellular trafficking and functional interactions in the primary cilium during murine postnatal cerebellum development. Furthermore we are investigating whether the Shh signalling pathway is altered in Gpr37l1 null mutant mice, by biochemical and histochemical analysis of several Shh-Smo effectors and targets.