Genetic ablation of Gpr37l1 delays tumor occurrence in Ptch1+/− mouse models of medulloblastoma

The G-protein coupled receptor 37-like 1 (Gpr37l1) protein is widely expressed by the Gpr37l1 gene in the cerebellar Bergmann glia astrocytes. Genomic and transcriptomic analyses have indicated that the expression of Gpr37l1 protein is upregulated in human glioma and glioblastoma and downregulated in both human and mouse medulloblastoma samples.

Gpr37l1 protein interacts with a membrane component of the sonic hedgehog (Shh) receptor complex known as patched 1 (Ptch1). However, the absence of this protein in mouse models alters the activation of Shh-smoothened (Smo) mitogenic signaling. This results in the premature down-regulation of granule neuron precursor proliferation and the concomitant development and maturation of Bergmann glia astrocytes and Purkinje neurons. Hence, affected mice exhibit precocious postnatal cerebellar development. Past studies have indicated that the dysregulated hyperproliferation of granule cell precursors in the external granular layer (EGL) of the cerebellum is characterized by the occurrence of postnatal Shh-associated medulloblastoma. Based on the interaction between Gpr37l1 protein and Ptch1 in Bergmann glia astrocytes, and the premature down-regulation of postnatal granule neuron precursor caused by the genetic inactivation of the Gpr37l1 gene, the authors of this study aimed at investigating the influence of Gpr37l1-mediated signaling in medulloblastoma oncogenesis using heterozygous (Ptch1^+/−) murine models.

To this effect, scientists at the Italian National Research Council (CNR) namely: Dr. Chiara Di Pietro, Dr. Gina La Sala, Dr. Rafaele Matteoni, Dr. Daniela Marazziti, and Dr. Glauco Tocchini-Valentini concerted efforts to demonstrate the influence of Gpr37l1 protein on the incidence and progression of medulloblastoma, using novel Gpr37l1, Ptch1 murine double mutant models. They discovered that the genetic ablation of Gpr37l1 delayed tumor occurrence in Ptch1^+/− mouse models. Their research work is published in Experimental Neurology.

The authors observed that the absence of Gpr37l1 protein significantly delayed tumor occurrence in Ptch1^+/− murine models. Despite the high prevalence of classic/desmoplastic tumor types in Ptch1^+/− murine models, the highly proliferating anaplastic tumors were absent in this mouse model. They also observed that the absence of Gpr37l1 protein delayed and drastically reduced the occurrence of hyperplastic cerebellar lesions in Ptch1^+/− murine models.

The absence of Gpr37l1 protein was found to have resulted in a significant reduction in granule cell precursor proliferation and EGL thickness, extensive expression of wingless-type MMTV integration site member 3 protein (a specific inhibitor of Shh-induced neuronal mitogenesis), and significant reduction in the level of glioma-associated oncogene family zinc finger 2 protein (a major transcriptional activator that mediates Shh mitogenic signaling) at the early stages of postnatal cerebellar development in Ptch1^+/− murine models.

The Italian research team’s findings provide clear evidence that the Gpr37l1 protein plays a specific role in the modulation of postnatal cerebellar Shh-Ptch1-Smo mitogenic signaling under normal and pathological conditions. The novel Gpr37l1^−/−, Ptch1^+/− murine models produced and analyzed in this study can be used in subsequent research studies for the detailed characterization and analysis of the initiation and development of Shh-associated medulloblastoma at the cytological and molecular level. Furthermore, the findings documented in this publication will advance further studies on the potential applications of Ptch1^+/− murine models in the study of novel clinical and pharmacological approaches.