title: Modelling cell cycle synchronisation in networks of coupled radial glial cells.
abstract: Radial glial cells play a crucial role in the embryonic mammalian brain. Their proliferation is thought to be controlled, in part, by ATP mediated calcium signals. It has been hypothesised that these signals act to locally synchronise cell cycles, so that clusters of cells proliferate together, shedding daughter cells in uniform sheets. In this paper we investigate this cell cycle synchronisation by taking an ordinary differential equation model that couples the dynamics of intracellular calcium and the cell cycle and extend it to populations of cells coupled via extracellular ATP signals. Through bifurcation analysis we show that although ATP mediated calcium release can lead to cell cycle synchronisation, a number of other asynchronous oscillatory solutions including torus solutions dominate the parameter space and cell cycle synchronisation is far from guaranteed. Despite this, numerical results indicate that the transient and not the asymptotic behaviour of the system is important in accounting for cell cycle synchronisation. In particular, quiescent cells can be entrained on to the cell cycle via ATP mediated calcium signals initiated by a driving cell and crucially will cycle in near synchrony with the driving cell for the duration of neurogenesis. This behaviour is highly sensitive to the timing of ATP release, with release at the G1/S phase transition of the cell cycle far more likely to lead to near synchrony than release during mid G1 phase. This result, which suggests that ATP release timing is critical to radial glia cell cycle synchronisation, may help us to understand normal and pathological brain development.
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: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D063928:Ependymoglial Cells / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Bifurcation analysis; Calcium dynamics; Cell cycle; Cell cycle synchronisation; Radial glial cells