Characterisation of the role of NG2-glia and microglia in hypothalamo-pituitary axis coupling.

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80% of children affected by cancer now survive, 5 years after detection of the disease, thanks to earlier diagnoses and better treatments. This is a great improvement. However, these children require extra levels of monitoring and care because they can be affected by sequelae of anti-cancer treatments. In particular, brain radiation therapies are associated with a lifelong risk to develop pituitary hormone deficiencies. This risk is high, as up to 50% of survivors present these deficiencies. The pituitary is a small gland located at the base of the brain. It is attached to the hypothalamus, the region in the brain that controls the secretion in the blood of the six hormones the pituitary synthetizes: Growth Hormone, necessary for growth, Prolactin that induces milk production, Thyroid Stimulating Hormone inducing thyroid hormones levels to increase, Adrenocorticotropic Hormone that regulates secretion of the stress hormone cortisol, Luteinizing and Follicle-stimulating hormones both regulating puberty and reproduction. Because of the diverse roles of the pituitary hormones, deficits are associated with significant adverse effects including thyroid hormone and cortisol deficiencies, puberty defects, growth delay and cognitive impairments. In adults, pituitary deficits are also observed after treatment by radiotherapy for brain tumours, although the clinical effects are less profound. We know that radiation mostly affect the dividing cells, which is why they are used in anti-cancer therapy; however, we do not know how they induce a decrease in pituitary hormone levels. Understanding how this happens would help finding preventive measures or cures to avoid these deficits in paediatric cancer survivors. In animal models such as rats, cranial irradiation is also associated with pituitary hormones deficits, so rodents are a good model to study this phenomenon. In mice, as in humans, radiation therapies are also linked with a risk to develop obesity. Recently, scientists have demonstrated in mice that if radiations are focalised to the region that links the pituitary to the hypothalamus, obesity develops. They found that, in this small domain, hypothalamic nerves that regulate appetite are not sensing gut signals anymore. This is because the cells that protect them, called NG2 glia, divide frequently and are destroyed by radiations. In our lab, we have discovered that mice in which the Sox3 gene has been removed develop pituitary hormone deficits, as human patients carrying mutations in SOX3. Strikingly, we observe that NG2-glia is affected in Sox3 mutants, in this same region that links the hypothalamus and pituitary. The immune system may play a role, because when we give aspirin, likely to affect the inflammatory response in this context, normal hormone levels are restored in Sox3 mutants. We do not know whether aspirin has a similar effect in patients carrying SOX3 mutations. The goal of our project is to investigate the role of NG2 glia and brain immune cells in the communication between the hypothalamus and pituitary. We want to investigate if destruction of these cells by radiations explain the risk of irradiated cancer patients to develop pituitary deficiencies. To test our hypotheses, we will specifically eliminate the NG2 glia in mice using a novel approach and measure pituitary hormones. Little is known about the NG2 glia in this region: we will therefore examine in details which cells the NG2 glia is in contact with to understand better what its function could be. In parallel, we will test the potential involvement of brain immune cells by ablating them with a known efficient and selective drug after irradiation, and in Sox3 mutants, to examine whether hormonal deficits still develop in their absence. Finally, we will investigate the effects of aspirin in mice to understand how it can cure mice carrying Sox3 mutations. We hope that ultimately our results will help preventing pituitary deficits in cancer survivors.