Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CYCLODE (Cyclical and Linear Timing Modes in Development)

Teaser

Organismal development requires proper temporal coordination of events such as cell differentiation, proliferation, and morphogenesis. The mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or...

Summary

Organismal development requires proper temporal coordination of events such as cell differentiation, proliferation, and morphogenesis. The mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or ‘clocks’, that control recurring events. Examples of repetitive developmental processes are the formation of the vertebrate spine from repetitive segments, or the molting of roundworms, which occurs regularly at the end of larval stages. Furthermore, it is unknown how clocks are started up and arrested, e.g. to ensure an appropriate number of cyclical repeats. We aim to elucidate the components, wiring, and properties of a prototypic developmental clock by studying developmental timing in the roundworm C. elegans. We build on our recent discovery that nearly 20% of the worm’s transcriptome oscillates during larval development. Our aims are i) to identify components of this clock, ii) to gain insight into the system’s architecture and properties, and iii) to understand the initiation and termination of clock cycles. As developmental timing genes and rhythmic gene expression are also important for controlling stem cell fates, we foresee that the results gained will additionally reveal regulatory mechanisms of stem cells, thus advancing our fundamental understanding of animal development and future applications in regenerative medicine.

Work performed

Our work relies on an ability to follow gene expression patterns and development at high temporal resolution, and ideally in parallel. Hence, we have established assays that enable us to track larval development at the single animal level but for many animals at the same time. This, together with sequencing-based analysis has enabled us to generate evidence that the gene expression oscillations in C. elegans are tightly coupled to development and indeed likely to control developmental progression. We have been able to screen for factors in which oscillations are compromised and are currently characterizing genes that we think encode oscillator components. Finally, our analyses have provided insights into oscillator properties.

Final results

Understanding developmental clocks and oscillators requires the availability of several systems to compare communalities and idiosyncrasies, to derive general concepts and unique implementations. It is only in this way that we can obtain a more than anecdotal understanding of how such dynamic systems function, and how we can manipulate them. Moreover, different systems provide different unique opportunities and tool, providing opportunities for unique insights. Our results have established C. elegans as a highly suitable system to study oscillations, using approaches not available in other organisms. This includes study of development and oscillatory gene expression at high temporal resolution and across many individual animals, and an ability to perform genetic screens for relevant factors. This enables mechanistic and quantitative insight into animal development at a level that has been possible previously. We note that the factors that we have thus far identified as candidate oscillator components are well conserved in mammals including humans, where they are cell fate-specifying factors and have been linked to diverse cancers and skin defects.