A molecular clock controls periodically driven cell migration in confined spaces.

Sung Hoon Lee, Jay C Hou, Archer Hamidzadeh, M Sulaiman Yousafzai, Visar Ajeti, Hao Chang, David J Odde, Michael Murrell, Andre Levchenko

Journal: Cell systems 2022;13(7):514-529.e10

PMID: 35679858

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Abstract

Navigation through a dense, physically confining extracellular matrix is common in invasive cell spread and tissue reorganization but is still poorly understood. Here, we show that this migration is mediated by cyclic changes in the activity of a small GTPase RhoA, which is dependent on the oscillatory changes in the activity and abundance of the RhoA guanine nucleotide exchange factor, GEF-H1, and triggered by a persistent increase in the intracellular Ca levels. We show that the molecular clock driving these cyclic changes is mediated by two coupled negative feedback loops, dependent on the microtubule dynamics, with a frequency that can be experimentally modulated based on a predictive mathematical model. We further demonstrate that an increasing frequency of the clock translates into a faster cell migration within physically confining spaces. This work lays the foundation for a better understanding of the molecular mechanisms dynamically driving cell migration in complex environments.

Address: Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.; Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Physics, Yale University, New Haven, CT 06520, USA.; Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Physics, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA.; Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. Electronic address: [email protected].

DOI: 10.1016/j.cels.2022.05.005