Molecular basis of cell cycle timers and their coordination during organogenesis

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Most animal species begin life as a single cell-a fertilized egg that repeats cell divisions to form their body. In the course of cell proliferation, the orchestration of cell division timings is critical for the formation and maintenance of tissues and organs. Although activators and inhibitors of cell division are known, the molecular mechanisms that precisely specify cell division timing remains a mystery in multicellular system. In our body, individual cells receive different physical and chemical information. Such tissue complexity is a substantial burden for cell division studies in multicellular organisms. Indeed, multicellular studies often end up finding correlation rather than causation. To overcome this problem, we will use a unique system that will efficiently and effectively help us understand the complexity of multicellular division. Our system has four strengths - first, the chosen model organism, the nematode C. elegans, has only 959 somatic cells, but is complex enough to form different tissues and organs; second, a number of genetic tools are available in C. elegans, thereby allowing us to search cell division regulators out of all ~20,000 genes of this animal; third, the timing and orientation of cell division are invariant among individual worms; this feature offers a great advantage to precisely understand the regulation of multicellular division at single-cell resolution; finally, we have recently developed a method to reconstitute and simplify the multicellular environment, using isolated embryonic cells and artificial beads, which will afford us an unprecedented advantage to understand the causal relationship between the multicellular environment and the timing of cell division. By taking advantages of our unique system, we will address the following questions: Q1: What are the molecular timers that specify cell division timing? Q2: How are cell division timings coordinated during organ formation? It is expected that the coordination of cell division timing is more critical in the development of functional multicellular assembly, such as organs. We will use the C. elegans intestine as a model organ. The C. elegans intestine is composed of only 20 cells originating from a single precursor cell called "E", the descendants of which divide at different times. We will - 1) precisely measure the activities of core cell division regulators in different cell types; 2) identify division timing modifiers required in specific cell types; 3) reveal a causal relationship between environmental signal and cell division timing by integrating multicellular-reconstitution assays, genetics, and live-imaging. Cell division regulators are remarkably similar among animals from worms to humans. Thus, our study using C. elegans should uncover the critical mechanisms that orchestrate multicellular division and animal development.