Variability of an early developmental cell population underlies stochastic laterality defects

Summary Embryonic development seemingly proceeds with almost perfect precision. However, it is largely unknown how much underlying microscopic variability is compatible with normal development. Here, we quantified embryo-to-embryo variability in vertebrate development, by studying cell number variation in the zebrafish endoderm. We noticed that the size of a sub-population of the endoderm, the dorsal forerunner cells (which later form the left-right organizer), exhibits significantly more embryo-to-embryo variation than the rest of the endoderm. We found that, when incubated at elevated temperature, the frequency of left-right laterality defects is increased drastically in embryos with a low number of dorsal forerunner cells. Furthermore, we observed that these fluctuations have a large stochastic component among fish of the same genetic background. Hence, a stochastic variation in early development leads to a remarkably strong macroscopic phenotype. These fluctuations appear to be associated with maternal effects in the specification of the dorsal forerunner cells.