Cortical development depends on the active integration of cell autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions.

The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models have provided insight into how the ChP–CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.

Extracranial metastasis is a unique but rare manifestation of glioblastoma multiforme. It is thought to arise from glioblastoma cells disseminated into the blood stream. We undertook a comprehensive analysis of 88 cases of extracranial glioblastoma (5 were gliosarcomas) published between 1928 and 2009. Cases included in the analysis were primary or secondary glioblastomas that subsequently invaded organs outside the brain or spinal cord. The median age was 38 years and the median overall survival time was 10.5 months (range 0.0-60.0 months). The median time from symptom onset to diagnosis of primary glioblastoma was 2.5 months, from diagnosis to detection of extracranial metastasis was 8.5 months, and from metastasis to death was 1.5 months. From 1940 to 2009, there has been progressive lengthening of the interval from detection of extracranial metastasis to death, at a rate of 0.7 months per decade (95% confidence interval 0.5-1.0 month). Use of magnetic resonance imaging correlates with an increase in overall survival but not age, gender, or site of primary glioblastoma. Patients treated with surgery + radiation + chemotherapy + cerebrospinal fluid shunting had the longest average survival interval from metastasis to death when compared to those treated with surgery alone, radiation alone, surgery + radiation, and surgery + radiation + chemotherapy. Lung metastasis is a prognostic factor of extremely poor outcomes. We conclude that patients with glioblastoma extracranial metastasis have poor prognosis, but there has been a progressive lengthening of survival in each successive decade from 1940 to 2000.

A sheet of choroid plexus epithelial cells extends into each cerebral ventricle and secretes signaling factors into the CSF. To evaluate whether differences in the CSF proteome across ventricles arise, in part, from regional differences in choroid plexus gene expression, we defined the transcriptome of lateral ventricle (telencephalic) versus fourth ventricle (hindbrain) choroid plexus. We find that positional identities of mouse, macaque, and human choroid plexi derive from gene expression domains that parallel their axial tissues of origin. We then show that molecular heterogeneity between telencephalic and hindbrain choroid plexi contributes to region-specific, age-dependent protein secretion in vitro. Transcriptome analysis of FACS-purified choroid plexus epithelial cells also predicts their cell-type-specific secretome. Spatial domains with distinct protein expression profiles were observed within each choroid plexus. We propose that regional differences between choroid plexi contribute to dynamic signaling gradients across the mammalian cerebroventricular system.

SUMMARY After neural tube closure, amniotic fluid (AF) captured inside the neural tube forms the nascent cerebrospinal fluid (CSF). Neuroepithelial stem cells contact CSF-filled ventricles, proliferate and differentiate to form the mammalian brain, while neurogenic placodes, which generate cranial sensory neurons, remain in contact with the AF. Using in vivo ultrasound imaging, we quantified the expansion of the embryonic ventricular-CSF space from its inception. We developed tools to obtain pure AF and nascent CSF, before and after neural tube closure, and define how the AF and CSF proteomes diverge during mouse development. Using embryonic neural explants, we demonstrate that age-matched fluids promote Sox2-positive neurogenic identity in developing forebrain and olfactory epithelia. Nascent CSF also stimulates Sox2-positive self-renewal of forebrain progenitor cells, some of which is attributable to LIFR signaling. Our resource should facilitate the investigation of fluid-tissue interactions during this highly vulnerable stage of early brain development.

The FDA's approval of bevacizumab for recurrent glioblastoma on May 9, 2009, was based on the significant response rate and clinical benefits seen from randomized phase II studies. Large-scale phase III data are unavailable. In an effort to determine benchmark efficacy parameters for bevacizumab and analyze its dose--response effect, the authors performed a meta-analysis of 15 studies published from 2005 to 2009, involving 548 patients with a median age of 53 years (range, 5-74 years), that used bevacizumab to treat recurrent glioblastoma. Median overall survival was 9.3 months (95% CI, 7.9-10.6 months). The respective 6-month progression-free and 6-month overall survival rates were 45% (95% CI, 34%-57%) and 76% (95% CI, 69%-84%), respectively. Median time to tumor progression was 6.1 months (95% CI, 4.2-8.1 months). The response analysis yielded a 6% complete response (95% CI, 2%-9%), 49% partial response (95% CI, 37%-61%), and 29% stable disease (95% CI, 20%-38%). No difference was seen in bevacizumab dose--response benefit between 5 mg/kg and 10 to 15 mg/kg. The efficacy benchmarks from this meta-analysis did not differ from those of the recently published randomized phase II studies. The lack of a dose--response effect would require confirmation in a prospectively conducted clinical trial.

Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumours by inducing sustained expression of Notch1 that recapitulate properties of human CP tumours with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumours, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues.

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