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Abstract

Asymmetric cell divisions play key roles in generating cellular diversity during embryogenesis, and in tissue homeostasis during postembryonic life. Particular asymmetric cell divisions producing differentially sized daughter cells were described in many systems, yet the importance of cell size asymmetry was demonstrated only in few cases. To further address this question, we used the C. elegans zygote that divides asymmetrically into a larger anterior AB cell and a smaller posterior P1 cell as a model of size asymmetric cell division. AB and P1 descendants give rise to vastly different tissues and organs in the worm body. Interestingly, cell size asymmetry of the first division is conserved in the Caenorhabditis genus spanning at least 100 million years of evolution. However, whether AB and P1 need to have unequal sizes to support normal C. elegans embryogenesis remains an open question. To generate embryos that will have the same size of AB and P1 without perturbing their anterior posterior polarity, we used a temperature-sensitive allele of lin-5, which governs asymmetric spindle positioning in the wild-type zygote. This LIN 5 protein variant can be reversibly inactivated by upshift to elevated temperature, allowing us to generate embryos with a range of relative AB/P1 sizes, including equalized embryos, and even inverted embryos with a smaller AB than P1. We then followed the development of such embryos at the permissive temperature using 3D timelapse microscopy followed by lineage tracing. We observed increasing lethality with decreasing size of AB, indicating that unequal cell size is vital for embryonic development of C. elegans. Furthermore, we found that inverted embryos with an AB size below 48% of total volume died in all cases, pointing to the existence of a clear size-asymmetry threshold for viability. Interestingly, we discovered that P1, but not AB, descendants exhibited accelerated cell cycles in equalized and inverted embryos. Moreover, we found that both cells originating from the anterior AB lineage and those of posterior P1 lineage end up in abnormal positions, or fail to express differentiation markers of endoderm and pharynx at wild-type levels or in a characteristic pattern. We uncovered markedly increased variability in timing, division orientation, and cell positions in equalized embryos, and even more so in those that eventually died. In conclusion, our results demonstrate that the size asymmetry of the first cleavage is necessary for the robust and stereotypic embryogenesis of C. elegans.

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