EMBL Seminars

Abstract
How morphogen gradients are formed has been under debate since the term was first coined by Alan Turing. Can diffusion alone lead to the robust formation of morphogen gradients? Or are cell processes like transcytosis important to move molecules across tissues? In this work we develop a theoretical framework to establish how the combination of different processes at the molecular and cellular level can in principle lead to morphogen gradient formation and its scaling to tissue size. We use this framework together with a sequence of independent experimental assays to quantify the relative contribution of different processes to the formation of the Dpp gradient in the fly wing. For large discs we find that a combination of hindered diffusion and recycling of endocytosed molecules drive Dpp gradient fromation. By studying wing discs of different sizes, we show that the relative contribution of endocytosed molecules to Dpp transport becomes progressively more pronounced during growth. Furthermore, the contribution of recycled molecules is diminished when the extracellular factor Pentagone is impaired. Our findings suggest that Pentagone modulates the contribution of recycled molecules to the diffusing pool. I will discuss potential mechanisms through which Pentagone encodes information about tissue size and their evolution.Finally, I will present a framework that takes into account cell and tissue architecture to ask how morphogenesis may impact the transport of morphogen molecules and patterning. 

About the speaker
Zena obtained a BA in Mathematics at Magdalene College, University of Cambridge, in 2004, and an MSc in Statistics at Stanford University in 2007. She went on to do an MRes and PhD in Mathematical Biology at UCL, studying the evolution of sexual differentiation. 
In 2014 she received an EPSRC Doctoral Prize Fellowship to study the role of cell-cell signalling in development and evolution. During this time she worked closely with experimental collaborators to study the role of Notch signalling in spatiotemporal pattern formation in the Drosophila notum and zebrafish spinal cord. 
She then moved at the University of Geneva and the Max Planck Institute for the Physics of Complex Systems in Dresden as an HFSP Long Term Fellow. As a postdoctoral fellow Zena studied morphogen gradient formation, and the machineries that allow morphogen gradients to scale to size during developmental growth. 
She joined the Francis Crick institute as a group leader in 2021, where her group studies growth and patterning in development and evolution through the lens of physics and mathematics. Zena holds a joint appointment at the Department of Physics and Astronomy at the University College London.

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Abstract
The spliceosome, a complex protein/RNA macromolecular machinery, removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to protein coding mRNAs and functional non-coding RNAs. In this talk I will illustrate how atomic-level simulations have contributed to elucidate: (i) the function of specific protein components of the spliceosome assembly [1,2]; (ii) the mechanism of pre-mRNA selection by selected splicing factors, and the impact of cancer associated mutation on pre-mRNA recognition [3]; (iii) the chemical details of pre-mRNA splicing [4,5], and (iv) the mechanism of spliceosome helicases [6]. [1] Casalino, L.; Palermo, G.; Spinello, A.; Rothlisberger, U.; Magistrato, A. All-atom simulations disentangle the functional dynamics underlying gene maturation in the intron lariat spliceosome. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, 6584 [2] Saltalamacchia, A.; Casalino, L.; Borišek, J.; Batista, V. S.; Rivalta, I.; Magistrato, A. Decrypting the Information Exchange Pathways across the Spliceosome Machinery. J. Am. Chem. Soc. 2020, 142, 8403. [3] Borišek, J.; Saltalamacchia, A.; Galli, A.; Palermo, G.; Molteni, E.; Malcovati, L.; Magistrato, A. Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations. Biomolecules, 2019, 9, 633. [4] Casalino, L.; Palermo, G.; Rothlisberger, U.; Magistrato A. Who activates the nucleophile in ribozyme catalysis? An answer from the splicing mechanism of group II introns J. Am. Chem. Soc. 2016, 138 (33), 10374 [5] Borišek, J.; Magistrato, A. All-Atom Simulations Decrypt the Molecular Terms of RNA Catalysis in the Exon-Ligation Step of the Spliceosome. ACS Catal. 2020, 10, 5328 [6] Movilla, S.; Roca, M.; Moliner, V.; Magistrato, A Molecular Basis of RNA-Driven ATP Hydrolysis in DExH-Box Helicases. J. Am. Chem. Soc. 2023, https://doi.org/10.1021/jacs.2c11980

About the speaker
Alessandra Magistrato is research director at of Italian National Research Council (CNR-IOM) c/o International School for Advanced studies, Trieste Italy, where she leads the group computational biology and drug discovery. She obtained her PhD at ETH Zentrum, Zuerich, Switerland, and she was postdoctoral fellow at the University of Pennsylvania, Philadelphia, PA, USA. Her research activity is devoted to the development and application of multi-scale molecular simulations to study protein/RNA machineries, metal ions transporters and cytolytic toxins and in the discovery of drugs targeting them.

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Connection details
Zoom*: https://embl-org.zoom.us/j/96986610968?pwd=d0lEb2NKakx1UVdycFd2TVZIdFgydz09

Meeting ID: 969 8661 0968
Passcode: 480991

Please note that the talk willnot be recorded.
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Connection details
Zoom*: [https://embl-org.zoom.us/j/3528126808?pwd=WEZuRXlZTG83MzgvV2FId1R3STVBUT09] (Meeting ID: [352 812 6808], Password: [2LCN7s])

*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.