Bmi1 overexpression in the cerebellar granule cell lineage of mice affects cell proliferation and survival without initiating medulloblastoma formation.

Hourinaz Behesti,Michael D Taylor,Silvia Marino,Adrian M Dubuc,Heeta Bhagat

doi:10.1242/dmm.009506

Abstract

SUMMARYBMI1 is a potent inducer of neural stem cell self-renewal and neural progenitor cell proliferation during development and in adult tissue homeostasis. It is overexpressed in numerous human cancers – including medulloblastomas, in which its functional role is unclear. We generated transgenic mouse lines with targeted overexpression of Bmi1 in the cerebellar granule cell lineage, a cell type that has been shown to act as a cell of origin for medulloblastomas. Overexpression of Bmi1 in granule cell progenitors (GCPs) led to a decrease in cerebellar size due to decreased GCP proliferation and repression of the expression of cyclin genes, whereas Bmi1 overexpression in postmitotic granule cells improved cell survival in response to stress by altering the expression of genes in the mitochondrial cell death pathway and of Myc and Lef-1. Although no medulloblastomas developed in ageing cohorts of transgenic mice, crosses with Trp53−/− mice resulted in a low incidence of medulloblastoma formation. Furthermore, analysis of a large collection of primary human medulloblastomas revealed that tumours with a BMI1high TP53low molecular profile are significantly enriched in Group 4 human medulloblastomas. Our data suggest that different levels and timing of Bmi1 overexpression yield distinct cellular outcomes within the same cellular lineage. Importantly, Bmi1 overexpression at the GCP stage does not induce tumour formation, suggesting that BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival.

Highlights

Medulloblastoma is a malignant paediatric cerebellar tumour that can arise from cerebellar granule cell progenitors (GCPs), as shown by conditional mouse models with compound homozygous mutations in Rb and Trp53 (Marino et al, 2000) or heterozygosity in patched1 (Ptch1) (Schuller et al, 2008; Yang et al, 2008)
In the mouse central nervous system (CNS), Bmi1 overexpression driven by the nestin promoter was shown to increase neural stem cell (NSC) self-renewal in vitro but not in vivo (He et al, 2009), whereas lentiviral overexpression in the embryonic and adult cortices as well as conditional overexpression in nestin-positive radial glial cells and progenitors derived thereof resulted in increased cell proliferation both in vitro and in vivo (Fasano et al, 2009; Yadirgi et al, 2011)
Human medulloblastoma is classified into four groups according to gene expression profiles; here, the authors found that human tumours with a BMI1high TP53low profile are significantly enriched in Group 4 human medulloblastomas

Summary

Introduction

Medulloblastoma is a malignant paediatric cerebellar tumour that can arise from cerebellar granule cell progenitors (GCPs), as shown by conditional mouse models with compound homozygous mutations in Rb and Trp (Marino et al, 2000) or heterozygosity in patched (Ptch1) (Schuller et al, 2008; Yang et al, 2008). Cerebellar granule cells, the most populous neuronal cell type of the mammalian central nervous system (CNS), originate from the upper rhombic lip upon expression of Math (atonal homologue 1), amongst other genes (Machold and Fishell, 2005; Wingate and Hatten, 1999) Upon specification, they migrate to form the external granule cell layer (EGL), where they proliferate extensively for up to 3 weeks, including the first two postnatal weeks in the mouse (Behesti and Marino, 2009). BMI1 is an epigenetic gene repressor (Valk-Lingbeek et al, 2004) expressed at high levels in human and mouse proliferating GCPs, and at low levels in postmitotic granule cells It is overexpressed in several human cancers, including medulloblastoma (Leung et al, 2004). Defined spatiotemporal overexpression of Bmi in a known cell of origin of a CNS tumour is required to understand the role of BMI1 overexpression in brain oncogenesis

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