Open research seminars

Who should attend?

All researchers and postgraduates with an interest in biosciences are welcome to attend.

Dr Steffen Scholpp, Karlsruhe Institute for Technology

The Wnt morphogenetic field - about ligand transport, advection and signaling

After secretion, developmental signals known as morphogens must travel relatively long distances to form a concentration gradient that the responding tissue uses to acquire positional information. The role of morphogen transport and endocytic trafficking in this process is the subject of intense debate. Wnt proteins regulate developmental processes, tissue regeneration and stem cell maintenance. It has been postulated that Wnt/β-catenin signalling form concentration gradients across responsive tissues and act as morphogens. However, little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates.

Here we show that Wnt8a is transported on short, actin-based filopodia to contact responding cells and activate signalling during neural plate formation in zebrafish (1). Cdc42/N-Wasp regulates the formation of these Wnt-positive filopodia. Enhanced formation of filopodia increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in filopodia leads to a restricted distribution of the ligand and a limited signalling range. Using a numerical simulation, we provide evidence that such a short-range transport system for Wnt has long-range signalling function.

After contact by Wnt/β-catenin positive filopodia, a multi-protein complex at the plasma membrane assembles clustering membrane-bound receptors and intracellular signal transducers into the so-called Lrp6-signalosome. Our imaging studies in live zebrafish embryos show that the signalosome is a highly dynamic structure, which is continuously assembled and disassembled by a Dvl2-mediated endocytic process (2). We show that this endocytic process is not only essential for ligand-receptor internalization but also for signaling.

We conclude that a cytoneme-based transport system for Wnt and subsequent endocytosis is important for Wnt/β-catenin signaling and controls anteroposterior patterning of the neural plate during vertebrate gastrulation.

Biography

Steffen is a research group leader in the Institute of Toxicology and Genetics at the Karlsruhe Institute for Technology. He has previously held positions at Kings College London and the Max Planck Institute.

Dr Elisabeth Busch, Sanger Institute

Exploring the transcriptional landscape of development and disease

Regulatory interactions between genes are the fundamental basis of embryonic development. There is growing evidence that in normal gene regulation protein levels are most strongly influenced by the amount of available transcript.

At the same time however, transcript levels can vary substantially even in apparently normal tissues or embryos. Equally, it is not clear to what extent differing transcript levels resulting from DNA sequence alteration or environmental disturbance can be tolerated before the whole system changes from normal to phenotypic. It is therefore of great interest to not only investigate gene relationships by measuring their transcriptional co-regulation, but to tie these profiles to a whole organism phenotypic readout.

We have developed a high-throughput mRNA 3’end sequencing method (DeTCT) that allows us to quantify mRNA levels of large numbers of individual genotyped zebrafish embryos under a variety of conditions. We also use conventional RNA-seq in mouse and zebrafish for in depth full length transcript analysis.

Examination of different embryonic stages in wild types and mutants has revealed layers of transcriptional changes and variation that are often independent from or precede morphological phenotypes. I will illustrate key findings from our studies using examples of mouse and zebrafish baseline profiling as well as mutant data.

Biography

After studying biochemistry at the Eberhard-Karls-University, Elisabeth Busch-Nentwich gained her PhD at the Max-Planck-Institute for Developmental Biology in Tübingen. During her time at the MPI she participated in one of the large forward mutagenesis screens in zebrafish with a focus on inner ear function. In 2003 she joined Derek Stemple’s team at the Wellcome Trust Sanger Institute as a postdoc modelling human myopathies in zebrafish and went on to establish a high-throughput reverse genetics effort as co-project leader of the Zebrafish Mutation Project. Elisabeth is now Head of Vertebrate Genetics and Genomics and her current work focuses on integrating morphological and molecular phenotyping approaches to elucidate regulatory pathways of development and disease.

Registration

Please email research-events@exeter.ac.uk if you wish to attend.