Computational modeling of the consequences of embryonic neurogenesis disorders
Résumé
To characterize how cell cycle-related defects can impact on mouse brain development, we have generated a simulation model that recapitulates the divisions of NSCs (Neural Stem Cells) during neurogenesis in silico. This model is based on cell cycle parameters of the progenitor populations
evaluated in normal brains over the neurogenesis period (E10 to P0).
To exemplify the use of our mathematical simulation, we have predicted the consequences of cell cycle perturbations due to centrosome amplification (the presence of more than two centrosomes in a cell) measured in a mouse model that we have recently generated and that exhibit microcephaly (brain size reduction). We have compared the brain volume reduction experimentally measured to the one simulated as a consequence of the observed defects that contribute to the depletion of the progenitor populations.
First, we took into account the mitotic delay observed at different developmental stages and second the fraction of progenitor cells undergoing apoptosis, as a result of multipolar divisions that generate unviable aneuploid progeny.
Our simulations provide evidence that depleting the fraction of NSCs undergoing multipolar divisions from the cycling population is sufficient to mimic over time the experimental curve and the extent of microcephaly that we observed during development. To further validate our scenario, we also tested the extent of microcephaly to be expected while considering that the whole population of NSCs with centrosome amplification at the onset of mitosis would be depleted. In such scenario, the extent of microcephaly predicted was much higher than what we observed experimentally; suggesting that brain size would be more reduced if all NSCs with extra centrosomes would die.
We concluded from this simulation that molecular mechanisms exist that enable normal NSC divisions in the presence of extra centrosomes. Indeed, we observed centrosome clustering mechanisms that favor bipolar spindle formation in the presence of extra centrosomes.
Our model allows to study the impact of cell cycle parameters during mammalian brain development. We believe this computational model could contribute to the identification of the mechanisms responsible for brain size reduction in the context of neurodevelopmental disorders.