Gene Expression Noise Enhances Robust Organization of the Early Mammalian Blastocyst

A critical event in mammalian embryo development is construction of an inner cell mass surrounded by a trophoectoderm (a shell of cells that later form extraembryonic structures). We utilize multi-scale, stochastic modeling to investigate the design principles responsible for robust establishment of these structures. This investigation makes three predictions, each supported by our quantitative imaging. First, stochasticity in the expression of critical genes promotes cell plasticity and has a critical role in accurately organizing the developing mouse blastocyst. Second, asymmetry in the levels of noise variation (expression fluctuation) of Cdx2 and Oct4 provides a means to gain the benefits of noise-mediated plasticity while ameliorating the potentially detrimental effects of stochasticity. Finally, by controlling the timing and pace of cell fate specification, the embryo temporally modulates plasticity and creates a time window during which each cell can continually read its environment and adjusts its fate. These results suggest noise has a crucial role in maintaining cellular plasticity and organizing the blastocyst.Author Summary: A critical event in mammalian embryo development is construction of a mass of embryonic stem cells surrounded by a distinct shell that later forms the placenta along with other structures. Despite sustained investigation, multiple hypotheses for what is responsible for this organization persist and it remains unclear what is responsible for the robust organization (remarkable ability for embryos to pattern correctly) of these structures. Here, we utilize multi-scale, stochastic modeling along with fluorescence imaging to investigate the factors that contribute to the incredible robustness of this organizational process. Results point to two factors that contribute to this robustness: 1) the timing and pace of cell fate specification and 2) stochastic gene regulatory effects. The former creates a window of time during which each cell can continually read their environment and adjust their gene expressions (and consequently fate) in response to dynamic rearrangements of cells arising from cell divisions and motions. The latter improves cell plasticity, providing the capability for cells to adjust to changes in their local environment. Fluorescence imaging results demonstrate that the magnitude and structure of gene expression variations match those predicted to promote organizational robustness.