Mechanical feedback drives asynchronous cell divisions during embryogenesis

The initial stage of zebrafish morphogenesis is characterized by a synchronous to asynchronous transition (SAT) in cell divisions. The cells divide in unison in the synchronous phase, unlike in the asynchronous phase. Despite the widespread observation of SAT in multiple organisms, there is no theoretical framework to predict the critical number of cell cycles <a:math xmlns:a="http://www.w3.org/1998/Math/MathML"><a:msup><a:mi>n</a:mi><a:mo>*</a:mo></a:msup></a:math> that mark the beginning of asynchronous division. Here, by probabilistically modeling cell cycle progression under the assumption that the distribution of cell division times is broadened, we predict the value of <b:math xmlns:b="http://www.w3.org/1998/Math/MathML"><b:msup><b:mi>n</b:mi><b:mo>*</b:mo></b:msup></b:math> and the time at which the SAT occurs. The theory, supplemented by agent-based simulations, supports the hypothesis that the SAT emerges as a consequence of biomechanical feedback on cell division. Our results are in excellent agreement with experiments while also explaining the cell cycle lengthening that arises as a result of biomechanical feedback. The emergence of the asynchronous phase is due to increasing fluctuations in the cell cycle times with each round of cell division. We also make several testable predictions that further shed light on the role of biomechanical feedback in growing multicellular systems, such as during tissue and tumor growth.