Geometric analysis of the Goldbeter minimal model for the embryonic cell cycle (Q264101)

The process of cell division constitutes a principal modelling challenge in cell biology [\textit{B. Alberts} et al., Molecular biology of the cell. New York: Garland Science (2014)]; the division cycle is typically modelled as a sequence of phases that include DNA replication and mitosis, the timing of which is governed by various classes of proteins. Here, the authors consider a minimal model for the embryonic cell cycle developed in [\textit{A. Goldbeter}, ``A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase'', Proc. Natl. Acad. Sci. USA 88, No. 20, 9107--9111 (1991; \url{doi:10.1073/pnas.88.20.9107})] which involves cyclin, cdc2 kinase, and a cyclin protease, and which displays oscillatory dynamics in certain parameter regimes. Motivated by numerical simulation, they prove the existence of a unique, strongly attracting limit cycle in the corresponding nonlinear three-dimensional system of ordinary differential equations. They show that the cycle is generated by relaxation oscillation in an auxiliary system which is singularly perturbed due to the presence of small Michaelis constants in the model. Their proof is perturbative, and is based on geometric singular perturbation theory [\textit{N. Fenichel}, J. Differ. Equations 31, 53--98 (1979; Zbl 0476.34034)] and the blow-up technique [\textit{F. Dumortier} and \textit{R. Roussarie}, Mem. Am. Math. Soc. 577 (1996; Zbl 0851.34057)]: a singular limit cycle is constructed, consisting of segments of slow flow near branches of a critical manifold which are connected by fast transitions between those branches. A novel phenomenon of exchange of stability is identified at lines of intersection between the branches of the critical manifold which involves a super-slow drift along those lines. Finally, the persistence of the singular limit cycle is proven for sufficiently small values of the relevant Michaelis constants by concatenation of the various scaling regimes found in the auxiliary system. Due to its general character, the geometric approach developed by the authors should be applicable to related models for cell cycle dynamics, thus paving the way for a systematic mathematical analysis of such models.