Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor

Abstract

In the developing cerebellum, the proliferation and differentiation of glial and neuronal cell types depend on the modulation of the sonic hedgehog (Shh) signaling pathway. The vertebrate Gprotein-coupled receptor 37-like 1 (GPR37L1) gene encodes a putative G-protein-coupled receptor that is expressed in newborn and adult cerebellar Bergmann glia astrocytes. This study shows that the ablation of the murine Gpr37l1 gene results in premature down-regulation of proliferation of granule neuron precursors and precocious maturation of Bergmann glia and Purkinje neurons. These alterations are accompanied by improved adult motor learning and coordination. Gpr37l1 −/− mice also exhibit specific modifications of the Shh signaling cascade. Specific assays show that in Bergmann glia cells Gpr37l1 is associated with primary cilium membranes and it specifically interacts and colocalizes with the Shh primary receptor, patched 1. These findings indicate that the patched 1-associated Gpr37l1 receptor participates in the regulation of postnatal cerebellum development by modulating the Shh pathway.mutant mouse model | mitogenic signaling

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“…However, in the NIH-3T3 cells, no co-localization of GPR37L1 WT or the K349N mutant with the cilia marker Arl13b was observed (Figure 2C). The lack of cilial targeting may be due to the differences in the cell type and/or culture method used in our studies versus the studies of Marazziti and colleagues 17 .…”

“…While Gpr37L1 has been shown to play a role in postnatal cerebellar development in a mouse model 17 , the overall function of this receptor is unknown. To assess the effect of the K349N mutation on the ability of GPR37L1 to express and traffic to the cell surface, we transiently expressed Flag-tagged versions of GPR37L1 wild-type (WT) or the K349N mutant receptor in HEK293T cells.…”

“…In these studies, the cleaved form of both GPR37L1 and the K349N mutant appeared to be enriched at the cell surface, but the physiological relevance of this observation is unknown. As Marazziti and colleagues 17 reported GPR37L1 to be localized to cilia in cerebellar Bergmann glial cells, we assessed the localization of GFP-tagged versions of each receptor in NIH-3T3 cells (Figure 2C), a cell type commonly used for studying cilia 41 . Both versions of the receptor were found predominantly on the cell surface and exhibited generally similar patterns of subcellular localization in confocal microscopy analyses.…”

“…These receptors share their strongest sequence similarity to the endothelin and bombesin receptors and other peptide-activated GPCRs and are thought to be activated by a yet-to-be-identified peptide ligand. Little is known about the function of GPR37L1, indeed, to date there is only one published report assessing the role of GPR37L1 in vivo 17 . In that study, mice lacking Gpr37L1 were found to have a modest alteration in postnatal cerebellar development, characterized by reduced granule cell precursor proliferation and early maturation of Bergmann glia and Purkinje cells 17 .…”

“…Little is known about the function of GPR37L1, indeed, to date there is only one published report assessing the role of GPR37L1 in vivo 17 . In that study, mice lacking Gpr37L1 were found to have a modest alteration in postnatal cerebellar development, characterized by reduced granule cell precursor proliferation and early maturation of Bergmann glia and Purkinje cells 17 . In contrast, GPR37 has been extensively studied for its association with Parkinson’s disease and role in dopaminergic signaling 18–24 .…”