Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.
More strikingly, L1TD1 depletion downregulated expression of the neural stem cell markers, CD133 and Nestin, inhibited neurosphere generation capability, and sensitized medulloblastoma cells to temozolomide and cisplatin, two chemotherapeutic agents of clinical relevance in medulloblastoma treatment.
To investigate the mechanisms of genetic interactions between Shh and IGF signaling in the cerebellum, we crossed nestin/IGF-I transgenic (IGF-I Tg) mice, in which transgene expression occurs in neuron precursors, with Ptc1+/- knockout mice, a model of medulloblastoma in which cancer develops in a multistage process.
Primary tumor cells derived from two models of murine medulloblastoma (Ptch1(+/-);Ink4c(-/-) and p53(FL/FL);Nestin-Cre(+); Ink4c(-/-)) that retain and lack p53 function, respectively, displayed a dependence on functional p53 to engage 17-DMAG-induced apoptosis.
Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice.