title: Modelling the coupling between intracellular calcium release and the cell cycle during cortical brain development.
abstract: Most neocortical neurons formed during embryonic brain development arise from radial glial cells which communicate, in part, via ATP mediated calcium signals. Although the intercellular signalling mechanisms that regulate radial glia proliferation are not well understood, it has recently been demonstrated that ATP dependent intracellular calcium release leads to an increase of nearly 100% in overall cellular proliferation. It has been hypothesised that cytoplasmic calcium accelerates entry into S phase of the cell cycle and/or acts to recruit otherwise quiescent cells onto the cell cycle. In this paper we study this cell cycle acceleration and recruitment by forming a differential equation model for ATP mediated calcium-cell cycle coupling via Cyclin D in a single radial glial cell. Bifurcation analysis and numerical simulations suggest that the cell cycle period depends only weakly on cytoplasmic calcium. Therefore, the accelerative impact of calcium on the cell cycle can only account for a small fraction of the large increase in proliferation observed experimentally. Crucially however, our bifurcation analysis reveals that stable fixed point and stable limit cycle solutions can coexist, and that calcium dependent Cyclin D dynamics extend the oscillatory region to lower Cyclin D synthesis rates, thus rendering cells more susceptible to cycling. This supports the hypothesis that cycling glial cells recruit quiescent cells (in G0 phase) onto the cell cycle, via a calcium signalling mechanism, and that this may be the primary means by which calcium augments proliferation rates at the population scale. Numerical simulations of two coupled cells demonstrate that such a scenario is indeed feasible.
authors.affiliation: Horizon Digital Economy Research Institute, University of Nottingham, Nottingham NG7 2TU, UK; School of Mathematical Sciences and Centre for Mathematical Medicine and Biology, University of Nottingham, Nottingham, UK. Electronic address: duncan.barrack@nottingham.ac.uk.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Barrack
authors.affiliation: School of Mathematical Sciences and Centre for Mathematical Medicine and Biology, University of Nottingham, Nottingham, UK.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Thul
authors.affiliation: School of Mathematical Sciences and Centre for Mathematical Medicine and Biology, University of Nottingham, Nottingham, UK.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Owen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D008962:Models, Theoretical
chemical_list: D002118:Calcium
keywords: Bifurcation analysis; Calcium dynamics; Cell cycle; Radial glial cells