5: Igf2+/+, 2.5 ± 0.3; Igf2−/−, 1.7 ± 0.1; Mann-Whitney; p < 0.05; n = 5). NeuN- and late-born Cux1-staining neurons were reduced in Igf2−/− mice ( Figure 5H and data not shown), confirming that Igf2 contributes to cortical progenitor proliferation and to late stages of neurogenesis. Taken together, our genetic experiments support a model in which the apical complex localizes Igf signaling in progenitors by ensuring the apical, ventricular

localization of the Igf1R. In this manner, the apical complex couples cell autonomous and extracellular check details signals to the regulation of cortical development. Our data, together with recent findings implicating Igf signaling in the maintenance of adult neural stem cells (Llorens-Martín et al., 2010), raised Selleckchem NVP-BKM120 the possibility that abnormalities of the CSF may be relevant to conditions showing abnormal proliferation, including in glioblastoma multiforme (GBM), a malignant astrocytic brain tumor. Igf-PI3K-Akt signaling has been

implicated as a key regulator of gliomagenesis (Louis, 2006 and Soroceanu et al., 2007), and mutations in PTEN are commonly found in patients with GBM ( Louis, 2006). We analyzed Igf2 concentration in a panel of 56 human GBM patient CSF samples collected from 21 individuals representing the full range of disease progression and 8 disease-free controls and found that CSF from GBM patients contained significantly more Igf2 than CSF from disease-free controls (Igf2 concentration expressed as mean ± SEM for GBM patients, 340.4 ± 12.9 ng/ml; DNA ligase n = 56; disease-free controls, 222.9 ± 41.5 ng/ml; n = 8; Mann-Whitney, p < 0.01). Three GBM samples containing the highest Igf2 concentrations (605.8 ng/ml, 502.8 ng/ml, and 468.7ng/ml) came from patients with advanced disease ( Figure 6A and Table 1). By contrast, the three patients with the lowest levels of Igf2 (142.1 ng/ml,

145.4 ng/ml, and 153.9 ng/ml) all had early or stable glioma ( Figure 6A and Table 1). Similar to rodent ventricular CSF, human lumbar CSF stimulated cortical progenitor cell proliferation in our explant assay, with CSF from GBM patients causing greater proliferation than CSF from disease-free controls ( Figure 6B). Moreover, human GBM patient CSF neutralized with Igf2 antibodies failed to stimulate the proliferation of progenitor cells ( Figure 6B; Igf2 concentration following NAb absorption, GBM1(PBS): 605.8 ng/ml; GBM1(NAb), 45.6 ng/ml; GBM2(PBS), 502.8 ng/ml; GBM2(NAb), 218.3 ng/ml; GBM3(PBS), 468.7 ng/ml; GBM3(NAb), 248.8 ng/ml). Taken together, these data suggest that beyond embryonic brain development, CSF-Igf2, in particular, is a potential mediator of GBM pathology and that the CSF mechanisms that normally regulate neural stem cells are misregulated in GBM.