Molecular mechanisms of metabolic rewiring in vivo during retinal neurogenesis of zebrafish

• Applicant: Helena Khaliullina, Ph.D.
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280662750

Metabolic rewiring, a shift of cellular energy production from oxidative phosphorylation towards aerobic glycolysis, has been associated with proliferation and differentiation in various contexts. Particularly, in cancer cells this process is known as the Warburg effect. It is therefore important to identify the molecular mechanisms that underlie metabolic rewiring. Recent work has shown that metabolic rewiring is associated with the normal development of tissues as cells progress from stem cells to committed progenitors to differentiated cells. However, the basis of metabolic rewiring in physiological conditions is not elucidated yet, since many of these studies have been performed in vitro. In my preliminary work in the host lab, I have established that the TOR and HIF-1alpha signalling pathways play a significant role during metabolic rewiring during retinal development. The aim of this proposed project is to investigate in vivo, in a well-characterised model of zebrafish retina, a) how metabolic states are associated with the developmental program, b) to find out what drives metabolic rewiring in retinal neurogenesis, and c) to assess the functional significance of the TOR and HIF-1alpha pathways in this process. I will qualitatively and quantitatively characterise the metabolic profiles of all developmental states (from quiescent stem cells, to rapidly proliferating progenitors, to fully differentiated neurons) in the course of whole retinal development. I will describe the dynamics of metabolic rewiring during the transitions between the developmental states, applying state-of-the-art techniques such as metabolomics and single-cell transcriptomics. I will investigate whether and how signalling pathways that are known to determine retinal development participate in regulation of metabolism in retinal cells. Thereby I will focus on the function of TOR and HIF-1alpha signalling pathways and characterise their activities and requirement for metabolic rewiring in vivo. Further, I will determine the role of these pathways in regulation of metabolism in response to environmental factors such as nutrition and oxygen availability. Overall, the results of this project will uncover how metabolic rewiring instructs correct developmental transitions, what are the underlying molecular mechanisms of this process and how do these mechanisms implicate responses to extrinsic cues in cells at different developmental states.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. William A. Harris