Mathematical Modeling of Cortical Neurogenesis Reveals that the Founder Population does not Necessarily Scale with Neurogenic Output

Abstract

The mammalian cerebral neocortex has a unique structure, composed of layers of different neuron types, interconnected in a stereotyped fashion. While the overall developmental program seems to be conserved, there are divergent developmental factors generating cortical diversity amongst species. In terms of cortical neuronal numbers, some of the determining factors are the size of the founder population, the duration of cortical neurogenesis, the proportion of different progenitor types, and the fine-tuned balance between self-renewing and differentiative divisions. We develop a mathematical model of neurogenesis that, accounting for these factors, aims at explaining the high diversity in neuronal numbers found across species. By framing our hypotheses in rigorous mathematical terms, we are able to identify paths of neurogenesis that match experimentally observed patterns in mouse, macaque and human. Additionally, we use our model to identify key parameters that would particularly benefit from accurate experimental investigation. We find that the timing of a switch in favor of symmetric neurogenic divisions produces the highest variation in cortical neuronal numbers. Surprisingly, assuming similar cell cycle lengths in primate progenitors, the increase in cortical neuronal numbers does not reflect a larger size of founder population, a prediction that has identified a specific need for experimental quantifications.

New insights into the development of the human cerebral cortex

“…Neuroepithelial stem cells (NPCs) produce all neural progenitor cells, with the duration and timing of progenitor cell division contributing both to the size of the resultant neocortex and the identities of its constituent cells (Picco et al. ). NPCs initially amplify their pool in fast cell cycle divisions, and enlarge the pool before they transform into ventricular radial glial progenitor cells (Fig.…”

A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration

“…Largely facilitated by changes in neural stem and progenitor cell dynamics, the mammalian neocortex has undergone remarkable modifications in size, structure, and neuronal number through evolution (Lui et al, 2011;Borrell and Reillo, 2012;Betizeau et al, 2013;Smart et al, 2002;Lewitus et al, 2014;Borrell and Gö tz, 2014;Sun and Hevner, 2014;Picco et al, 2018). In the ventricular zone (VZ), apical progenitors, collectively composed of neuroepithelial cells and apical radial glia (aRG), divide to both self-renew and generate neurons (via an intermediate cell population) that migrate centrifugally to populate the cortical plate (Rakic, 1988;Malatesta et al, 2000;Noctor et al, 2001Noctor et al, , 2004Haubensak et al, 2004).…”

A mathematical insight into cell labelling experiments for clonal analysis

“…Population‐level models are well suited to capture large‐scale variations between cortices in different species (Picco et al. ), or to quantify differences between mutant and wild‐type cortices (Hsu et al. ).…”