Abstract
The developmental gene OTX2 is expressed by cerebellar granule cell precursors (GCPs), a cell population which undergoes massive expansion during the early postnatal period in response to sonic hedgehog (Shh). GCPs are thought to be at the origin of most medulloblastomas, a devastating paediatric cancer that arises in the developing cerebellum. OTX2 is overexpressed in all types of medulloblastomas, except in Shh-dependent type 2 medulloblastomas, although it has GCPs as cell-of-origin. This has led to the current view that OTX2 is not involved in tumorigenesis of this subgroup. How OTX2 might contribute to normal or tumoral GCP development in vivo remains unresolved. Here, we have investigated, for the first time, the physiological function of this factor in regulating proliferation and tumorigenesis in the developing mouse cerebellum. We first characterized Otx2-expressing cells in the early postnatal cerebellum and showed that they represent a unique subpopulation of highly proliferative GCPs. We next performed in vivo loss-of-function analysis to dissect out the role of Otx2 in these cells and identified a novel, Shh-independent, function for this factor in controlling postnatal GCP proliferation and cerebellum morphogenesis. Finally, we addressed the function of Otx2 in the context of type 2 medulloblastomas by directing Shh-dependent tumour formation in Otx2+ cells of the developing cerebellum and assessing the effects of Otx2 ablation in this context. We unravel an unexpected, mandatory function for Otx2 in sustaining cell proliferation and long-term maintenance of these tumours in vivo, therefore bringing unpredicted insight into the mechanisms of type 2 medulloblastoma subsistence. Together, these data pinpoint, for the first time, a crucial Shh-independent role for Otx2 in the control of proliferation of normal and tumoral granule cell precursors in vivo and make it an attractive candidate for targeted therapy in Shh-dependent medulloblastomas.
Highlights
Cerebellum development in mammals is characterized by postnatal transit amplification of granule cell precursors (GCPs), leading to tremendous numbers of granule neurons (80 billion in humans) in mature cerebellum[1]
Otx2+ and Otx2− progenitors could readily be separated by fluorescenceactivated cell sorting (FACS) analysis based on GFP expression, with Otx2+(GFP+) cells representing around 40% at P7 (Fig. 1d)
We report that Otx[2] is expressed in a subpopulation of GCPs with higher proliferative index, located in the mostposterior part of the postnatal cerebellum and that Otx[2] ablation in these cells impairs their proliferation through a sonic hedgehog (Shh)-independent, direct effect on the cell cycle
Summary
Cerebellum development in mammals is characterized by postnatal transit amplification of granule cell precursors (GCPs), leading to tremendous numbers of granule neurons (80 billion in humans) in mature cerebellum[1]. Shh stimulates the expression of the transcription factor N-Myc, which has recently been shown to exert a critical function in promoting GCP proliferation through the upregulation of cyclin-D2 expression[6,7,8]. Shh-induced extended proliferation of GCPs make them vulnerable to malignant transformation and explains why they constitute the cell of origin for different groups of medulloblastomas[9]. Genetic and molecular analyses of these tumours have identified dysfunction of signalling pathways that promote mitogenic stimulation of cerebellar precursors or their growth arrest after transit amplification[10]. Murine models harbouring some of these alterations develop type 2 medulloblastoma, confirming that they constitute common drivers for tumour formation[10]
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