背景:小鼠大脑皮层中的神经发生涉及两种主要类型的祖细胞的协调分裂,谁的数字,分裂模式和细胞周期持续时间设置最终的神经元输出。为了了解这些因素在神经发生过程中的各自作用,我们将体内实验研究与神经祖细胞动力学的数学建模和数值模拟相结合。特别关注中间祖细胞(IP)的数量,转运扩增祖细胞类型与最终神经元池的大小密切相关。
结果:描述IP动力学的多尺度形式主义允许人们跟踪细胞在细胞周期后续阶段的进展,以及不同细胞数量的时间演变。我们的模型考虑了参与神经发生的顶端祖细胞(AP)的分裂,神经源性和增殖性IPs,和新生的神经元。从一个群体到另一个群体的转移率受分裂模式(增殖,或神经原性),并且可能是时变的。模型输出成功地拟合了来自皮质发育不同阶段的小鼠胚胎的实验细胞数,考虑到IP和神经元,以调整数值参数。我们提供了有关细胞动力学的其他信息,如有丝分裂和S期指数,和神经源性分数。
结论:将该模型应用于Ftm/Rpgrip1l的小鼠突变体,一个与人类纤毛病变有严重脑异常的基因,揭示了神经发生期的缩短,与神经发生中期的顶端祖细胞的新生IP流入增加有关。我们的模型可用于研究具有皮质神经发生缺陷的其他小鼠突变体,并可适用于研究祖细胞动力学在皮质进化和人类疾病中的重要性。
BACKGROUND: 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.
RESULTS: 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 (proliferative, or 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. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction.
CONCLUSIONS: 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. 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.