Abstract
SUMMARYTerminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinate differentiation commitment and cell cycle exit are not yet understood. Using live, single-cell imaging of cell cycle progression and differentiation commitment during adipogenesis, we show that a rapid switch mechanism engages exclusively in G1 to trigger differentiation commitment simultaneously with permanent exit from the cell cycle. We identify a molecular competition in G1 between when the differentiation switch is triggered and when the proliferative window closes that allows mitogen and differentiation stimuli to control the balance between terminally differentiating cells produced and progenitor cells kept in reserve, a parameter of critical importance for enabling proper development of tissue domains and organs.
Highlights
Terminal differentiation is essential for developing, maintaining, and regenerating tissues in humans and other multi-cellular organisms and is the mechanism by which neurons, skeletal muscle cells, adipocytes, and many other critical cell types are generated (Ruijtenberg and van den Heuvel, 2016)
We validate that a threshold in PPARG levels can be used as a live-cell readout for the precise time when a cell commits to terminally differentiate
We showed that PPARG levels are predictive of final fate independently of when cells pass the threshold for terminal differentiation and that cells with higher PPARG levels maintain a higher probability to differentiate at different time points throughout adipogenesis (Figure 1E)
Summary
Terminal differentiation is essential for developing, maintaining, and regenerating tissues in humans and other multi-cellular organisms and is the mechanism by which neurons, skeletal muscle cells, adipocytes (fat cells), and many other critical cell types are generated (Ruijtenberg and van den Heuvel, 2016). A main bottleneck in understanding the relationship between cell cycle exit and terminal differentiation is the great variability in whether and when individual progenitor cells in the same population proliferate or differentiate during the several-day-long differentiation process, making it difficult to answer timing questions using traditional bulk cell approaches. To overcome this challenge, methods are needed that can simultaneously track cell cycle and differentiation progression live in individual cells in order to measure whether and when during the multi-day differentiation time course an individual cell commits to irreversibly differentiate. Such live-cell imaging studies for terminal cell differentiation have to our knowledge not yet been made
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