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Quantitative Biology of Developmental Ras/ERK Signaling: From Molecules to Morphologies

Speaker: Yogesh Goyal
Series: Final Public Oral Examinations
Location: Eisenhart Room (E-Quad G201)
Date/Time: Friday, September 15, 2017, 2:00 p.m. - 3:30 p.m.

Precision, reproducibility, and robustness are hallmarks of animal development.  How are such desirable properties imparted to the biological systems? At the same time, certain perturbations to inductive signals can derail development leading to abnormal outcomes. Such perturbations are often a result of alterations in the chemical properties, and thus the normal function, of signaling networks. Can we identify causal relationships between the nature of perturbations and the emergent abnormalities?  In this thesis, we attempt to answer these fundamental questions for patterning driven by the conserved Ras signaling network. We focus on the early embryonic patterning in Drosophila melanogaster, an experimental system uniquely suited for quantitative and high-throughput analyses.

In the first part of this thesis, we developed an optogenetic system for activating ERK, a Ras pathway readout. This enabled us to probe the differential contributions of dose, duration and spatial range of ERK activity on development. Remarkably, we found that embryogenesis is robust to ectopic ERK activation, except from 1-4 h postfertilization when perturbing the spatial extent of ERK activation leads to dramatic patterning disruptions. The second part of the thesis is motivated by a growing number of studies reporting that germline mutations in the Ras pathway components give rise to developmental abnormalities, collectively called RASopathies. Studies in cultured cells have demonstrated that these abnormalities may be caused by altered Ras signaling, but the nature of changes in developing tissues remains unknown.  We quantified spatiotemporal changes in ERK activity caused by such mutations in fixed Drosophila embryos. Surprisingly, we discovered that these mutations can both increase and reduce the levels of active ERK. The sign of the effect depends on cellular context, implying that some of the emerging RASopathies phenotypes may be caused by increased, as well as attenuated, levels of Ras signaling. Going beyond the analysis of fixed embryos, we describe a parallel live-imaging approach that can significantly increase the quantitative resolution of ongoing studies of the Ras pathway mutations.
Together, our findings have broad implications for the basic understanding of a large class of abnormalities and present rational guidelines for thinking about their origins and potential treatment.