A caspase–RhoGEF axis contributes to the cell size threshold for apoptotic death in developing Caenorhabditis elegans

Abstract

A cell’s size affects the likelihood that it will die. But how is cell size controlled in this context and how does cell size impact commitment to the cell death fate? We present evidence that the caspase CED-3 interacts with the RhoGEF ECT-2 in Caenorhabditis elegans neuroblasts that generate “unwanted” cells. We propose that this interaction promotes polar actomyosin contractility, which leads to unequal neuroblast division and the generation of a daughter cell that is below the critical “lethal” size threshold. Furthermore, we find that hyperactivation of ECT-2 RhoGEF reduces the sizes of unwanted cells. Importantly, this suppresses the “cell death abnormal” phenotype caused by the partial loss of ced-3 caspase and therefore increases the likelihood that unwanted cells die. A putative null mutation of ced-3 caspase, however, is not suppressed, which indicates that cell size affects CED-3 caspase activation and/or activity. Therefore, we have uncovered novel sequential and reciprocal interactions between the apoptosis pathway and cell size that impact a cell’s commitment to the cell death fate.

Quantitative cell morphology inC. elegansembryos reveals regulations of cell volume asymmetry

“…In our dataset, an amount of 93 sister cell pairs with one non-apoptotic cell and one apoptotic cell are recorded without data point loss at both their first appearances in at least one C. elegans wild-type embryo sample. It’s found that the majority of apoptotic cells (78 out of 93 sister cell pairs, >80%) acquire both smaller average volume and surface area than those of their sister cells right after the cytokinesis of their mother cells, reproducibly among embryo samples and regardless of lineal origin (Figure 6C; Figure 6D; Figure S18; Table S12); these quantitative results mean that the initial cell size asymmetry between an apoptotic cell and its sister cell, previously reported in specific population like neuroblast, is actually at work in a global manner throughout C. elegans embryogenesis [Cordes et al, Development , 2006; Sethi et al, PLoS Biol. , 2022].…”

“…, 2018]. Another previously studied relationship is the small cell size and apoptotic cell fate [Cordes et al, Development , 2006; Sethi et al, PLoS Biol. , 2022]; taking two C. elegans embryonic apoptotic cells, MSpaapp and ABprpppppa, as examples, the former proceeds apoptosis as soon as it’s produced while the latter is first involved in the development of spike tail and then proceeds apoptosis at very late stage [Sulston et al, Dev.…”