Figure 1. Tumor Suppressor Inactivation in Nestin-expressing Neural Stem/Progenitor Cells Induces High Grade Astrocytoma Formation.

A–B. Nestin-creER^T2 transgenic mice possess cre recombinase activity in the neural stem/progenitor niches. A. Representative images of X-gal-stained adult brain sections show that cre activity of nestin-creER^T2;R26-lacZ mice treated with tamoxifen at E13.5 recapitulates that of the hGFAP-cre transgenic mice. Scale bar, 2 mm. B. Representative images of X-gal-stained brain sections at 6 months post-injection (MPI) reveal that tamoxifen induction at 4 weeks of age mainly restricted cre activity to neural stem cells and their progeny in the subventricular zone (SVZ), rostral migratory stream (RMS) and olfactory bulb (OB), as well as in the subgranular zone and granule cell layer of the dentate gyrus in the hippocampus (HP). Transgene expression is also found in the cerebellum. No staining is found in the adult cortex (CTX) or striatum (ST), or in vehicle-treated mouse brains. Scale bar, 2 mm. C. Mice with induced tumor suppressor inactivation (nestin-creER^T2;Nf1^flox/+;p53^flox/flox;Pten^flox/+ or nestin-creER^T2;Nf1^flox/flox;p53^flox/flox) by tamoxifen treatment (TMX) have shortened survival compared to vehicle-treated (Veh) mice. Kaplan-Meier survival curves of nestin-creER^T2 mice with tumor suppressor inactivation induced at either E13.5 or 4 weeks of age show median survivals of 16 weeks and 46 weeks, respectively. Red arrow indicates timing of adult injection. D. Histologically identifiable high grade astrocytomas develop in inducible mutant mice. Representative H&E-stained brain sections reveal formation of brain tumors in nestin-creER^T2 mice with tumor suppressor inactivation induced at either E13.5 or 4 weeks of age. Grade III or IV astrocytomas with characteristic features of nuclear atypia, mitoses (arrowheads), and necrosis (N) are shown. Scale bars, 100 μm. E. Tumors express traditional markers of astrocytomas, including Ki67, Gfap, nestin, and Olig2. Scale bar, 100 μm.