Thursday, February 1, 2018 - 11:30
MSI Small Lecture Theatre
Professor Kate Storey FRSE FMedSci
Dr Martin Baron
University of Manchester
Understanding the connections between genotype and phenotype remains an important and challenging research problem in biology and medicine today. The Notch gene in Drosophila, encodes a highly modular developmental signalling receptor with widespread roles in development and adult tissue homeostasis. In Drosophila, historical studies have revealed the complex genetic architecture of Notch, comprising a diverse allelic series with intriguing tissue specificities and varying degrees of Notch loss or gain of function. More recently this genetic complexity is being recapitulated by 100's of human Notch mutations, uncovered through cancer genome sequencing. This diverse collection of mutations now provides an important resource to probe Notch structure/function and regulation. However much of this diversity is not easily interpretable at a structure/function level in terms of straightforward alterations to the core canonical Notch activation mechanism. Work in my group, combining genetic, cell biological and computational approaches, has revealed how a network of endocytic trafficking routes, including novel ligand-independent signal activation mechanisms, acts to tune Notch signalling levels in response to environmental and other signalling inputs. I will discuss our current work that is revealing how endocytic regulation further shapes altered signal outputs resulting from different classes of Notch mutant allele. The new work is shedding light on decades old unsolved problems arising Notch genetic analyses.
Martin Baron graduated from Oxford University in 1986 with a BA degree in Biochemistry. He then studied for a DPhil in structural biology at Oxford in the research group of Iain Campbell. In his DPhil he elucidated representative structures by NMR of different modular domains, which comprise many extracellular proteins. Structural work on EGF-like modules led to his interest in the developmental signalling protein Notch. In 1990, following award of his DPhil, Martin switched fields, joining the group of Spyros Artavanis-Tsakonas at Yale, to use genetic approaches in Drosophila to identify novel Notch regulators. This work highlighted the role of ubiquitin-ligase proteins in controlling Notch activity. In 1994 Martin joined the faculty of the University of Manchester. His research continues to utilise Drosophila as a model system to understand the regulation of Notch signalling outputs and to explain the mechanistic connections between genotype and phenotype. The focus of his work is to understand how endocytic networks shape Notch signalling outputs and modulates phenotypic outcomes of diverse Notch alleles.