Otx2 promotes granule cell precursor proliferation and Shh-dependent medulloblastoma maintenance in vivo

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.

Spatially aware dimension reduction for spatial transcriptomics

“…3d ). Otx2 encodes orthodenticle homeobox 2, a transcription factor that shapes the morphogenesis of the cerebellum through controlling the proliferation of postnatal granule cell precursors 43 . The middle GCL sublayer is enriched with the marker gene Cbln3 , which is predominantly expressed in mature granule cells that have ceased division and finished migration into the GCL 44 .…”

Spatially Aware Dimension Reduction for Spatial Transcriptomics

“…Specifically, the outer GCL sublayer is adjacent to the Purkinje cell layer and is enriched with the marker gene Otx2 (Figure 3g). Otx2 encodes orthodenticle homeobox 2, a transcription factor that shapes the morphogenesis of cerebellum through controlling the proliferation of postnatal granule cell precursors 40 . The middle GCL sublayer is enriched with the marker gene Cbln3 , which is predominantly expressed in mature granule cells that have ceased division and finished migration into the GCL 41 .…”

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

“…Chromatin accessibility is altered in medulloblastoma, where histone modifications may allow for increased OTX2 expression, and hence a positive feedback loop for OTX2 ( Wortham et al, 2014 ). Recent studies have also shown OTX2 is potentially required for tumor proliferation in the SHH group, although not necessarily for tumor formation ( El Nagar et al, 2018 ). In Group 3 medulloblastoma, OTX2 represses PAX3 and PAX6.…”