Teresa bridges two of the Institute’s research programmes, being jointly appointed to both the Epigenetics and Signalling programmes.
How do organisms keep track of time and what determines the lifespan of a species? The mechanisms that underlie biological timing remain largely unknown. Despite the high conservation of genetic programs throughout the animal kingdom, the duration of embryogenesis and lifespan are species-specific. For instance, mouse development lasts around 20 days, and the embryonic period of human gestation takes place during the first 60 days of pregnancy. This differences in timing arise at conception, as the progression from the fertilized zygote to embryo implantation lasts around four days in mouse whereas it takes seven days in human. Further, some species can halt development for extended periods of time (diapause) with no apparent trade-offs for development or lifespan.
Our lab studies the regulatory and dynamic processes that control timing in development and homeostasis across and within species with the long-term goal to modulate biological timing in a precise and tunable manner. Our current research questions are:
We make use of comparative human and mouse stem cell models as well as embryos to search for the regulatory mechanisms that determine species-specific timing. The lab employs genetic and pharmacological manipulations and quantitative and temporally resolved techniques such as flow cytometry, imaging, and genome-wide approaches to investigate the molecular and metabolic mechanisms that regulate developmental timing.
Overall, the identification of physiological mechanisms that modulate timing and its translation to stem cell models may have important implications in the field of human assisted reproduction, regenerative medicine, and aging. Changing the pace of developmental processes may facilitate the generation of clinically relevant cell types faster or it may allow lifespan extension.
The spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly distinct neuronal subtypes generated in a characteristic spatiotemporal arrangement from progenitors in the embryonic neural tube. To gain insight into the diversity and complexity of cells in the developing human neural tube, we used single-cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie stages (CS) CS12, CS14, CS17 and CS19 from gestational weeks 4-7. Analysis of progenitor and neuronal populations from the neural tube and dorsal root ganglia identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with mouse revealed overall similarity of mammalian neural tube development while highlighting some human-specific features. These data provide a catalogue of gene expression and cell type identity in the human neural tube that will support future studies of sensory and motor control systems. The data can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.
Time is inherent to biological processes. It determines the order of events and the speed at which they take place. However, we still need to refine approaches to measure the course of time in biological systems and understand what controls the pace of development. Here, we argue that the comparison of biological processes across species provides molecular insight into the timekeeping mechanisms in biology. We discuss recent findings and the open questions in the field and highlight the use of systems as tools to investigate cell-autonomous control as well as the coordination of temporal mechanisms within tissues. Further, we discuss the relevance of studying tempo for tissue transplantation, homeostasis and lifespan.
Although many molecular mechanisms controlling developmental processes are evolutionarily conserved, the speed at which the embryo develops can vary substantially between species. For example, the same genetic program, comprising sequential changes in transcriptional states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the program runs more than twice as fast in mouse as in human. This is not due to differences in signaling, nor the genomic sequence of genes or their regulatory elements. Instead, there is an approximately two-fold increase in protein stability and cell cycle duration in human cells compared with mouse cells. This can account for the slower pace of human development and suggests that differences in protein turnover play a role in interspecies differences in developmental tempo.
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