Growth control

The unifying theme encompassing the work of my lab is to understand how growth and patterning are regulated. The work on Wnt signaling and tumorigenesis are facets of this. Other facets include the size control and tissue fitness.

Dpp

An important open question in biology is how size control is achieved. The morphogen Decapentaplegic (Dpp) provides an ideal entry point to approach this question and delineate an intrinsic growth program down to its molecular basis. We have continually refined our understanding by applying state of the art technologies to rigorously interrogate the role of Dpp in growth. This work is ongoing.

Cell Competition

Cell competition is a process by which otherwise viable cells are actively eliminated due to the presence of more competitive cells. It is a conserved phenomenon and occurs in various developmental and experimental contexts. Competitive elimination represents a safeguard mechanism that potentiates animal development. However, the process can also be hijacked, for example, by cancer cells to promote and sustain malignancy. The elucidation of the interplay between loser and winner cells in the process of cell competition will provide new targets for the development of cancer therapeutics. An important step forward was the discovery that in established models of cell competition specific components of the evolutionarily ancient and conserved innate immune system are used to eliminate “unfit” Drosophila cells. We are continuing to refine our understanding of cell competition and working to integrate these insights into a holistic model of cell competition and tissue fitness. 

Theoretical/Mechanical Forces

Mathematical models describe systems in a quantitative manner, can simulate their behavior and hence may predict unseen properties. We are using mathematical modelling to probe the potential role of mechanical forces in growth control. In addition we are devising experimental approaches to be able to provide experimental data to refine the models and to challenge hypotheses that might arise from these models.

This effort has been carried out in close collaboration with the group of Christof Aegerter and was part of the Systems X initiative.

http://www.physik.uzh.ch/en/groups/aegerter.html

http://www.systemsx.ch/

Selected References

Aegerter-Wilmsen, T., Heimlicher, M.B., Smith, A.C., Reuille, P.B. de, Smith, R.S., Aegerter, C.M., and Basler, K. (2012). Integrating force-sensing and signaling pathways in a model for the regulation of wing imaginal disc size. Development (Cambridge, England) 139, 3221-3231.

Meyer, S.N., Amoyel, M., Bergantiños, C., La Cova, C. de, Schertel, C., Basler, K., and Johnston, L.A. (2014). An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science (New York, N.Y.) 346, 1258236.

Müller, B., Hartmann, B., Pyrowolakis, G., Affolter, M., and Basler, K. (2003). Conversion of an extracellular Dpp/BMP morphogen gradient into an inverse transcriptional gradient. Cell 113, 221-233.

Restrepo, S., Zartman, J.J., and Basler, K. (2014). Coordination of patterning and growth by the morphogen DPP. Current biology : CB 24, R245-55.

Schwank, G., Dalessi, S., Yang, S.-F., Yagi, R., Lachapelle, A.M. de, Affolter, M., Bergmann, S., and Basler, K. (2011a). Formation of the long range Dpp morphogen gradient. PLoS biology 9, e1001111.

Schwank, G., Restrepo, S., and Basler, K. (2008). Growth regulation by Dpp: an essential role for Brinker and a non-essential role for graded signaling levels. Development (Cambridge, England) 135, 4003-4013.

Schwank, G., Tauriello, G., Yagi, R., Kranz, E., Koumoutsakos, P., and Basler, K. (2011b). Antagonistic growth regulation by Dpp and Fat drives uniform cell proliferation. Developmental cell 20, 123-130.