The time taken for cells to complete a round of cell division is a stochastic process controlled, in part, by intracellular factors. These factors can be inherited across cellular generations which gives rise to, often non-intuitive, correlation patterns in cell cycle timing between cells of different family relationships on lineage trees. Here, we formulate a framework of hidden inherited factors affecting the cell cycle that unifies known cell cycle control models and reveals three distinct interdivision time correlation patterns: aperiodic, alternator and oscillator. We use Bayesian inference with single-cell datasets of cell division in bacteria, mammalian and cancer cells, to identify the inheritance motifs that underlie these datasets. From our inference, we find that interdivision time correlation patterns do not identify a single cell cycle model but generally admit a broad posterior distribution of possible mechanisms. Despite this unidentifiability, we observe that the inferred patterns reveal interpretable inheritance dynamics and hidden rhythmicity of cell cycle factors. This reveals that cell cycle factors are commonly driven by circadian rhythms, but their period may differ in cancer. Our quantitative analysis thus reveals that correlation patterns are an emergent phenomenon that impact cell proliferation and these patterns may be altered in disease.
The current manuscript is a computational study, so no data have been generated for this manuscript. Modelling code is uploaded to gitHub https://github.com/fernhughes/Lineage-tree-correlation-pattern-inference.
Research data supporting Cell size control driven by the circadian clock and environment in cyanobacteriaApollo - University of Cambridge Repository.
Supplementary Data 2 supporting Hidden heterogeneity and circadian-controlled cell fate inferred from single cell lineagesNature Communications, Supplementary Data.
Mycobacteria Modify Their Cell Size Control under Sub-Optimal Carbon SourcesMiles Priestman shared the raw data.
- Fern A Hughes
- Alexis Barr
- Philipp Thomas
- Alexis Barr
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Arvind Murugan, University of Chicago, United States
- Received: June 9, 2022
- Accepted: November 14, 2022
- Accepted Manuscript published: November 15, 2022 (version 1)
© 2022, Hughes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Different organelles traveling through neurons exhibit distinct properties in vitro, but this has not been investigated in the intact mammalian brain. We established simultaneous dual color two-photon microscopy to visualize the trafficking of Neuropeptide Y (NPY)-, LAMP1-, and RAB7-tagged organelles in thalamocortical axons imaged in mouse cortex in vivo. This revealed that LAMP1- and RAB7-tagged organelles move significantly faster than NPY-tagged organelles in both anterograde and retrograde direction. NPY traveled more selectively in anterograde direction than LAMP1 and RAB7. By using a synapse marker and a calcium sensor, we further investigated the transport dynamics of NPY-tagged organelles. We found that these organelles slow down and pause at synapses. In contrast to previous in vitro studies, a significant increase of transport speed was observed after spontaneous activity and elevated calcium levels in vivo as well as electrically stimulated activity in acute brain slices. Together, we show a remarkable diversity in speeds and properties of three axonal organelle marker in vivo that differ from properties previously observed in vitro.
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