Living organisms constantly face situations of feast and famine. Energy homeostasis mechanisms help to deal with changes in nutrient availability, adjusting development, growth, and reproduction. The maintenance of energy homeostasis in multicellular organisms relies on nutrient sensing pathways that signal in a cell non‑autonomous manner to coordinate growth and development across tissues.
In our laboratory we use the postembryonic developmental programm of C. elegans as a model to study how nutrient sensing pathways control cell proliferation and arrest. We have a special focus in L1 arrest, a starvation-induced reversible arrest at the first larval stage. We use L1 arrest as a model to study the mechanisms involved in ageing and in maintenance of the proliferation potential during cell quiescence.
Projects
Mechanisms for cell quiescence maintenance and recovery in Caenorhabditis elegans
In this project we are studying the molecular mechanisms controlling cell quiescence and its return to proliferation. To approach this problem we use an emergent model for the study of cell quiescence and reactivation, namely the developmental arrest of Caenorhabditis elegans as L1 larvae. This model allows us to study quiescence in an in vivo environment using a model organism amenable to genetic manipulation. When C. elegans embryos hatch in starvation, cell divisions become arrested and the animals remain at the beginning of the first larval stage (L1). Feeding of the larvae provokes the reinitiation of cell proliferation. However, the division of a group of blast cells that initiates C. elegans postembryonic development is delayed after a prolonged period of quiescence. Reduced insulin signalling ameliorates the effects of prolonged starvation, and these animals show a higher proliferation potential after extended starvation.
We will search for mechanistic insights into the process of maintenance of proliferation potential and recovery. These processes involve lysosomal function, modulation of the accumulation of Reactive Oxygen species and protein aggregates and regulation of cell cycle inhibitors but the connection between them remains elusive. In this project, we will mechanistically connect these findings to produce a model for the role of insulin signalling in the process of proliferation after prolonged cell quiescence.
Control of cell proliferation by nutrient sensing pathways
Insulin is one of the main metabolic regulators that connect the detection of nutrients with cell proliferation. The mitogenic effects of insulin are fundamentally mediated by its interaction with the RAS-MAPK/ERK pathway (Rat Sarcoma -Mitogen- Activated Protein Kinase/ERK). This project aims to elucidate mechanistic connections between IIS (Insulin / IGF-like signalling) and RAS signalling in the control of cell proliferation. These pathways have important implications in the relationship between diabetes and cancer.
The biological model that we use to approach this study is the post‑embryonic development of the model organism Caenorhabditis elegans. This system combines the advantages of the use of a tractable genetic system, with the complexity of a multicellular organism. Using a novel method to analyse development, we have unveiled a transient developmental arrest in C. elegans that is mediated by insulin and RAS signalling. We are using this quantifiable phenotype to dissect the connection between these pathways. Furthermore, we are investigating the mechanisms involved in the control of cell proliferation by IIS and RAS. The control of the progression of the development and cellular divisions exerted by the insulin receptor in conjunction with the RAS pathway is a relevant process for human health, since the failure of the cell cycle control mechanisms is directly involved in the onset of cancer.
C. elegans development and L1 arrest
In the nematode Caenorhabditis elegans, the complete developmental process has been described in detail and it´s extremely reproducible. The lineage of all the cells from egg to adult was traced by direct observation of the animals (Sulston & Horvitz 1977). The progression along postembryonic development is controlled by the heterochronic gene pathway in a process that has been described in detail (reviewed in (Rougvie & Moss 2013)). For this reason, the nematode offers a tractable model system to study nutritional control of development in a multicellular organism. In particular, the postembryonic development of C. elegans is subjected to nutritional control at several stages. C. elegans postembryonic development starts ex utero, when the eggs hatches and the first larvae (L1) appears. The newly hatched larvae have 558 cells, and about 10% of these cells divide further to reach the 959 somatic cells of the adult. Somatic cell divisions end with the transition to adulthood. The first nutritional control is exerted soon after hatching; the first larval stage (L1) will arrest if food is absent from the environment. This arrest involves quiescence of the blast cells that would normally divide to progress to the second larval stage. Arrested L1 can survive several weeks without food and show increased resistance to stress (Baugh 2013). Larval development is triggered when food is available, and the animals progress through four discrete larval stages (L1- L4) before reaching adulthood.
The transitions between larval stages are called molts (M1-M4) (Rougvie & Moss 2013; Singh & Sulston 1978. During the molting process the larvae show behavioural quiescence, form a plug of extracellular material and stop taking in food. Behavioural quiescence has been described as a sleep-like state (Raizen et al. 2008). In parallel to the process of molting, an extensive gene network of approximately 20% of the genes expressed during development shows an oscillation with the same period as that of the molting cycle (Hendriks et al. 2014; Kim et al. 2013).
Our research is funded by
