A major challenge in biology is to understand how buds comprising a few cells can give rise to complex plant and animal appendages like leaves or limbs. We address this problem through a combination of time-lapse imaging, clonal analysis, and computational modeling. We arrive at a model that shows how leaf shape can arise through feedback between early patterns of oriented growth and tissue deformation. Experimental tests through partial leaf ablation support this model and allow reevaluation of previous experimental studies. Our model allows a range of observed leaf shapes to be generated and predicts observed clone patterns in different species. Thus, our experimentally validated model may underlie the development and evolution of diverse organ shapes.

Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.

While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

Maintenance of stem cell properties is associated with reduced proliferation but it is unknown whether the transition kinetics through distinct cell cycle phases influences the function of HSCs. Mende et al examine the effects of increasing two cell cycle complexes CCND1–CDK4 and CCNE1–CDK2 on the transition kinetics of human HSCs and their maintenance and functional alterations in vivo.

Mammalian cell proliferation is controlled by mitogens. However, how proliferation is coordinated with cell growth is poorly understood. Here we show that statistical properties of cell lineage trees -the cell-cycle length correlations within and across generations -reveal how cell growth controls proliferation. Analyzing extended lineage trees with latent-variable models, we find that two antagonistic heritable variables account for the observed cycle-length correlations. Using molecular perturbations of mTOR and MYC we identify these variables as cell size and regulatory license to divide, which are coupled through a minimum-size checkpoint. The checkpoint is relevant only for fast cell cycles, explaining why growth control of mammalian cell proliferation has remained elusive. Thus, correlated fluctuations of the cell cycle encode its regulation.

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