Pten deletion in neonatal brain induces an abnormal neural progenitor niche that can synergize with Trp53 loss to generate medulloblastoma

To investigate Pten function in neonatal developing brain, we conditionally inactivated Pten in neural stem/progenitor cells at birth using a Nestin-CreER transgenic driver. Pten inactivation created a novel perivascular proliferative niche in the cerebellum that did not progress to malignancy during the lifespan of the mouse. Co-deletion of Pten and Trp53 synergized to cause fully penetrant medulloblastoma originating from a perivascular niche. The Pten and Trp53 double knock-out medulloblastomas showed an extensive and abnormal blood vessel network and advanced neuronal differentiation of tumor cells compared to medulloblastomas arising in Nestin-creER;Trp53fl/fl mice, suggesting that Pten loss promoted angiogenesis and neuronal differentiation in medulloblastoma. EdU pulse-chase experiments demonstrated a lineage hierarchy of the double knock-out medulloblastomas consistent with a perivascular cancer stem cell population. The Pten and Trp53 double knock-out medulloblastomas showed somatic loss of chromosomes 7, 13 and 16, and inactivating mutations in the tumor suppressor gene Ptch1. Gene expression profiles showed that this model recapitulated the subgroup of human medulloblastomas with de-regulated SHH signaling. Copy number changes of this Medulloblastoma model was investigated using aCGH for 18 tumors. Gene expression profiling was done using Affymetrix HG-U133 plus 2 arrays for 6 tumors, 3 mouse brain with Pten wildtype at P5, 3 mouse brain with Pten null at P5, 3 mouse brain at adult age. The double knockout mouse are mixed background of FVB and C57BL/6.