P75^NTR induces apoptosis in medulloblastoma cells

The classic medulloblastoma (CMB) and the desmoplastic medulloblastoma (DMB) subtypes represent the major medulloblastoma variants. In contrast to CMB, DMB display high levels of the low-affinity nerve growth factor receptor p75^NTR. Given the reports of a better clinical course of DMB, we hypothesized that p75^NTR might act as a tumor suppressor in medulloblastomas. In a large set of medulloblastomas, p75^NTR was screened for mutations, and its mRNA expression and the DNA methylation status of its 5′-region were assessed. p75^NTR immunostainings were performed in wild-type murine cerebella and medulloblastomas arising in patched heterozygous mice, and murine cerebellar granule cell precursors (GCP) were analyzed in vitro. Medulloblastoma cells engineered to express p75^NTR were characterized flow cytometrically and morphologically. One CMB displayed a mutation of the p75^NTR coding sequence. p75^NTR mRNA levels clearly delineated DMB and CMB; however, CpG island hypermethylation was excluded as the cause of low p75^NTR expression in CMB. Sonic Hedgehog-treated GCP showed elevated p75^NTR expression, and strong expression of p75^NTR was detected in the external granule cell layer of wild-type mice and in murine ptc^± medulloblastomas. CMB cells overexpressing p75^NTR displayed a significant increase in apoptosis. In summary, our data link activated Hedgehog signaling in DMB with p75^NTR expression and characterize p75^NTR as a biologically relevant inductor of apoptosis in MB.