A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

Abstract : Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. A multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (symmetric, asymmetric, neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Additional information is provided on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases. 2 Introduction The multiple functions of the mammalian cerebral cortex in integrating sensory stimuli, controlling motor output and mediating cognitive functions are supported by an extraordinary diversity of neuronal sub-types mutually connected through complex neuronal circuitry. The formation of this structure requires producing the correct numbers and subtypes of neurons at the proper position during a specific period
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Marie Postel, Alice Karam, Guillaume Pézeron, Sylvie Schneider-Maunoury, Frédérique Clément. A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex. BMC Bioinformatics, BioMed Central, 2019, 20 (1), ⟨10.1186/s12859-019-3018-8⟩. ⟨hal-01783141v2⟩

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