PT  - JOURNAL ARTICLE
AU  - Michael L. Zhao
AU  - Atefeh Rabiee
AU  - Kyle M. Kovary
AU  - Zahra Bahrami-Nejad
AU  - Brooks Taylor
AU  - Mary N. Teruel
TI  - Regulation of the time when cells commit to terminally differentiate controls the number of differentiated cells
AID  - 10.1101/632570
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 632570
4099  - http://biorxiv.org/content/early/2020/01/20/632570.short
4100  - http://biorxiv.org/content/early/2020/01/20/632570.full
AB  - Terminal cell differentiation is essential for developing and maintaining tissues in all multi-cellular organisms. However, when and how the opposing processes of proliferation and terminal cell differentiation regulate permanent exit from the cell cycle and the number of differentiated cells is not well understood. Here we use adipogenesis as a model system to measure in live single cells the moment of terminal cell differentiation during cell-cycle progression. We show that terminal cell differentiation occurs through a competition during a lengthening G1 phase whereby cells either commit to terminally differentiate and close the window of proliferation, or commit to the next cell cycle and extend the window of proliferation until a later G1 phase. By regulating when cells terminally differentiate, different strengths of mitogen and differentiation stimuli control the number of terminally differentiated cells produced per progenitor cell. Together, our study suggests that tissue development, maintenance and regeneration is regulated by a competition mechanism that speeds up or delays the time when cells commit to terminally differentiate.HIGHLIGHTSProgenitor cells decide to terminally differentiate by using a competition process that can last over multiple cell cycles and engages during each lengthening G1 phaseThe cyclin-CDK inhibitor p21 is induced by PPARG and extends G1 duration, and also triggers permanent cell-cycle exit once PPARG reaches the threshold for terminal differentiationThe system architecture regulates the number of differentiated cells by speeding up or delaying the time when cells commit to terminally differentiate and close the window of proliferation