Olfactory sensory experience regulates gliomagenesis via neuronal IGF1.

Animals constantly receive various sensory stimuli, such as odours, sounds, light and touch, from the surrounding environment. These sensory inputs are essential for animals to search for food and avoid predators, but they also affect their physiological status, and may cause diseases such as cancer. Malignant gliomas-the most lethal form of brain tumour1-are known to intimately communicate with neurons at the cellular level2,3. However, it remains unclear whether external sensory stimuli can directly affect the development of malignant glioma under normal living conditions. Here we show that olfaction can directly regulate gliomagenesis. In an autochthonous mouse model that recapitulates adult gliomagenesis4-6 originating in oligodendrocyte precursor cells (OPCs), gliomas preferentially emerge in the olfactory bulb-the first relay of brain olfactory circuitry. Manipulating the activity of olfactory receptor neurons (ORNs) affects the development of glioma. Mechanistically, olfaction excites mitral and tufted (M/T) cells, which receive sensory information from ORNs and release insulin-like growth factor 1 (IGF1) in an activity-dependent manner. Specific knockout of Igf1 in M/T cells suppresses gliomagenesis. In addition, knocking out the IGF1 receptor in pre-cancerous mutant OPCs abolishes the ORN-activity-dependent mitogenic effects. Our findings establish a link between sensory experience and gliomagenesis through their corresponding sensory neuronal circuits.

Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting.

Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells-of-origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin-like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new-generation brain-penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.

[Expression of follistatin, activin A and BMP-4 in rats with hypoxic-ischemic brain damage].

OBJECTIVE: To investigate the expression and significance of follistatin, activin A and bone morphogenetic protein-4 (BMP-4) in normal brain tissues of rats and the brain tissues with hypoxic and ischemicgin. METHODS: Sixty conception SD rats were divided into normal and model group (with 30 for each). According to the development of fetal rats in each group, they were randomly divided into six subgroups (embryonic stage 8. 5 d, 13 d, 18 d (E8.5,E13,E18), and after the birth 3 d, 7 d and 30 d (P3,P7,P30), five fetal or young rats in each subgroup. Hypoxic-ischemic brain model was established. Expressions and origins of follistatin, activin A and BMP-4 with hypoxic-ischemic brain damage were determined by immunohistochemical and RT-PCR methods. RESULTS: In normal group, follistatin and activin A protein expressed at a very low level and gradually decreased with the period of fetal development when evaluated with immunohistochemical and RT-PCR methods; almost no expression of BMP-4 was detected in embryonic but a little bit of expression at 30 d after the birth. In hypoxic-ischemic brain damage group, the expression of follistatin, activin A and BMP-4 was significantly higher than those in normal group (P < 0.01). CONCLUSION: The expression of Follistatin, activin A and BMP-4 are related to developmental time, the expression of follistatin, activin A and BMP-4 is highly increased after cerebral ischemia and hypoxia injury. This implies that the main function of follistatin is as the inhibitor of activin A instead of the ligland of BMP-4 to regulate neural development.