How can cells can actually sense or measure intracellular distances, or can they use such mechanisms for cell size or length regulation?
We combined computational modeling and experimental approaches to propose a new mechanism for cell size/length sensing, based on motor driven frequency based signaling (Rishal et al., 2012). Two salient attributes of the mechanism are robustness arising from the frequency-based rather than quantity-based nature of the signal, and simplification of the spatial complexity of the problem due to directional restriction of signal propagation to the cytoskeleton.
The latter attribute essentially distils the three-dimensional problem of cell size sensing to a one-dimensional solution, bringing an intriguing new perspective to a fundamental problem in cell biology.
|The top schematics depict the main features of the model, while the lower schematic shows an experimentally validated prediction. For further details please see Rishal et al., 2012.|
More recently, we demonstrated that that motor-dependent mRNA localization regulates neuronal growth and cycling cell size (Perry et al., 2016). We found that the RNA-binding protein nucleolin is associated with importin β1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin β1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin β1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells.
Our current efforts in this research line are focused on understanding how subcellular regulation of RNA localization enables cell size sensing and cell growth regulation. We are examining the mechanisms underlying subcellular localization of nucleolin, trying to identify nucleolin cargo RNAs required for size sensing, and taking different approaches to elucidate links between localized translation, size sensing and growth control.