Variability of an early developmental cell population underlies stochastic laterality defects

Embryonic development seemingly proceeds with almost perfect precision. However, it is largely unknown how much microscopic variability is hidden beneath this macroscopic accuracy. 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 forms the left-right organizer), is highly variable between individual embryos. We found that the frequency of left-right laterality defects is increased drastically in embryos with a low number of dorsal forerunner cells, and we observed that these fluctuations are largely stochastic. Hence, a stochastic variation in early development leads to a remarkably strong macroscopic phenotype. These fluctuations appear to be caused by variable deposition of maternal factors involved in specification of the dorsal forerunner cells. In summary, we here dissect cause and consequence of embryo-to-embryo variability in a vertebrate model. Overall design: Transcriptomic comparison of Individual embryos from two zebrafish strains (AB and TL) at 2.25, 3.25, 4.25 and 5.25 hpf with two biological replicates.