Modulation of Endogenous TSC Signalling during Kidney Development
Final Report Abstract
The molecular mechanisms governing early pronephric development have been extensively investigated. Recent publications used high-end live cell imaging techniques to demonstrate how segments of the early pronephros form their shapes and move into proper position. Our research now helps to understand the time frame, which is connected to these early developmental events. The findings presented here, clearly demonstrate a pivotal role of the mTOR pathway in growth control of the late proximal tubules, i.e. the initiation and maintenance of the growth curve is a consequence of active mTOR signal transduction. Furthermore we demonstrate that miRNAs potentially control signal activity of this pathway by targeting one of the main negative regulators, Tsc1. This finding is consistent with a recent publication from the Wessley lab demonstrating that Dicer-MO injected tadpoles grow smaller proximal tubules. With this report here we now are able to understand the underlying developmental mechanisms, which contributes to this phenotype. As we have demonstrated active mTOR signal transduction is the main pathway that controls growth of the proximal tubules. But which regulatory mechanisms contribute to down regulation of the mTOR pathway and with that determine the final organ size is completely uninvestigated. There are multiple possibilities to follow up: (i) Cells stop growing and differentiate because they are deprived of energy (e.g. glucose) or (ii) lipids to built membranes or (iii) amino acids. We already ruled out the easiest explanation, that Insulin and Igf2 are no longer secreted during later stages. It will be interesting in the future to shift the focus towards the actual growth control problem. As we have described that mTOR signaling is responsible for organ growth control of the frog pronephric kidney and also have connected miRNAs to this process, right now the focus is on translating these findings into mouse methanephric development.
