Because of the very high sensitivity of the developing brain to DNA damage, exposure of foetuses to moderate and high doses (>300 mGy) of ionizing radiation during a critical period of neurogenesis affects brain development, leading to a reduction in brain size (microcephaly) and mental retardation. This is the main reason for the implementation of very strict radiation protection policies for pregnant women (both workers and patients). Our laboratory and others have modeled these effects of radiation in rodents showing very similar outcomes.
However, although rodents are excellent models for human brain development, they are by no means perfect. Human brains are characterized by an extremely high density of neurons and a very large relative cortex-to-brain volume. This results from the presence and specific properties of large numbers of outer radial glial cells (a type of intermediate neuron progenitors) in the human foetal brain that are very scarce in rodents. Also cell cycle properties are very different, which partly explains the difference in the timing of neurogenesis between both species (i.e. one week in mice versus three months in humans).
To better address certain aspects of human brain development, a new model has recently been developed which is the in vitro culture of human mini-brains or brain organoids derived from human induced pluripotent stem cells. These are complex three-dimensional structures that self organize and contain all cell types present in a human foetal brain, including outer radial glia. Importantly, several groups have shown that brain organoids are very suitable to mimic brain developmental defects such as microcephaly induced by the Zika virus or by deficiencies in DNA repair systems. For obvious reasons, the effects of prenatal irradiation on foetal brain development cannot be investigated in human subjects. Therefore, brain organoids are the closest model to the human foetal brain that is available for such kind of research and may help to better translate experimental findings to radiation protection policy.
This project will aim (i) to identify effects of radiation exposure on the growth of human brain organoids at different time points of their development, (ii) to identify molecular and cellular changes using a panel of high-throughput (single-cell) analysis methods (epigenomics, transcriptomics, proteomics), fluorescence microscopy and radio-imaging for cellular and functional markers, and (iii) to decipher underlying mechanisms for the changes observed using reverse genetics techniques.