Gpr37l1 regulates Shh signaling in cerebellar primary astrocytes.

The vertebrate G-protein coupled receptor 37 and 37-like 1 (GPR37 and GPR37L1) genes encode 7-transmembrane span proteins, with amino acid sequence homology to G-protein coupled receptors for the endothelin and bombesin peptides. Mammalian GPR37L1 proteins are specifically expressed in cerebellar Bergmann glia (BG) astrocytes and take part in regulating postnatal cerebellar granule neuron proliferation-differentiation and BG and Purkinje neuron maturation. The murine Gpr37l1 putative receptor co-localizes and interacts with patched1 (Ptch1), a sonic hedgehog (Shh) associated-receptor, in peri-ciliary membranes of BG cells. Primary cilia are microtubule-structured organelles that extend from glial and neuronal cell's surface and are crucially involved in pre-and postnatal cerebellar development, with activation and modulation of the Shh-Ptch1-smoothened (Smo) mitogenic signaling pathway. We are currently studying Gpr37l1-Ptch1 functional interactions in primary cerebellar astrocytes, from wild-type or Gpr37l1 null mutant pups. Primary astroglial cells of different genotype were prepared at postnatal day 7 and cultured to compare their proliferative states. Intracellular trafficking and localization of mitogenic ciliary components were monitored upon administration of Shh or related proliferation inhibitors/stimulators, (including a recently identified Gpr37l1 inverse agonist). The experimental results showed that the genetic ablation of Gpr37l1 results in increased production and secretion of Shh by cultured primary cerebellar astrocytes, in comparison with wild-type control cultures, with associated alteration of Shh-induced cell proliferation and Ptch1, Smo intracellular trafficking and ciliary localization.