Host: Dr Rastko Sknepnek 

Venue:  Sir Kenneth and Lady Noreen Murray Seminar Room, CITR 284, Discovery Centre

Abstract: 

 In development and disease, coordinated cell and tissue movement is crucial for processes like morphogenesis, immune response, and cancer invasion. While it is commonly assumed that collective motion is steered by pre-patterned chemical or mechanical cues, limited evidence supports such long-range guidance in living organisms. In contrast, recent findings are unveiling the prominence of local, self-generated cues across different systems, prompting a shift towards investigating controlled vs. self-organized guidance. In this talk I will focus on two distinct systems to explore their guidance principles: (i) The development of branched structures, such as neurons and lymphatic networks, and (ii) collective migration of immune cells. I will introduce theoretical models to predict quantitative signatures of self-organized vs. controlled guidance, which I will compare with experimental data at both cell and tissue scales. Finally, I will discuss the potential of self-organized guidance as a robust mechanism to navigate heterogeneous cell populations and to ensure tissue-scale optimization strategies. 

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Hosts: Ralitsa Madsen and Dario Alessi

Venue: SLS, Small Lecture, MSI

Abstract:

The MAPK/ERK and the PI3K/Akt pathways are among the major transducers of tyrosine receptor signalling, and play major roles in development, homeostasis and cancer. Recently, fluorescent biosensors of ERK and Akt activity have unveiled the temporal dynamics of these two pathways at the single cell resolution.

Thanks to these molecular tools, we discovered that apoptotic cells trigger collective ERK/Akt activity waves which radially propagate to the neighbouring cells in epithelial systems. These waves control epithelial homeostasis by coordinating the spatiotemporal occurrence of apoptotic events. We have also found that ERK activity waves control mammary acini morphogenesis. In this context, the ERK activity waves serve as a geometrical cue that coordinates single-cell ERK pulse frequency in space and time, organizing the lumen formation of mammary acini. In an epithelial cancer model, we show that the PIK3CA H1047R oncogene triggers oncogenic ERK waves. These waves alter mammary acini morphogenesis, promote growth factor-independent cell cycle progression, and resistance to chemotherapy. Currently, we are exploring how to target ERK activity waves to improve the response to therapy against cancer.

 In summary, by studying the dynamics of the ERK and Akt activity pathway at the single-cell resolution, we shed light on elusive collective signalling waves that play a major role in tissue homeostasis, morphogenesis, and cancer. This demonstrates the inherent power to study the dynamics of signalling transduction at the single-cell resolution.

Bio:

Paolo Armando Gagliardi completed his studies in Biomolecular Sciences and obtained his PhD in Molecular Medicine from the University of Torino in Italy in 2012. During his PhD and postdoc, he conducted research at the Candiolo Cancer Institute, a cancer research hospital near Torino. This work was carried out under the supervision of Prof. Luca Primo, where he focused on studying the role of kinases and integrins in various aspects of cancer, including tumour growth, cancer cell migration, invasion, epithelial homeostasis, molecular angiogenesis, and the response to targeted therapies. Since 2017, he has been working at the University of Bern in Switzerland, under the supervision of Prof. Olivier Pertz. At the University of Bern, he has studied single-cell signalling dynamics using fluorescent biosensors and optogenetics. Notably, his research led to the discovery of waves of ERK and Akt kinase activity that control epithelial homeostasis and 3D morphogenesis. Additionally, he has contributed to the development of methods for exploring and analysing single-cell signalling trajectories.

Host: Prof Geoff Barton

Venue: MSI , Small Lecture Theatre, SLS.

Abstract 

 At the heart of many cellular processes, microtubule filaments are responsible for actively organizing the cellular interior, enabling directed intracellular transport and providing force stroke during cell division. The latter is achieved by the mitotic spindle, primarily using microtubules that exert forces on kinetochore complexes attached to the chromosomes. Microtubules are nature’s most prominent self-assembling molecular machines and literally the quintessence of how complex physiological functions emerge from the self-assembly of simple protein 'building blocks' called tubulins. Microtubules grow by the addition of GTP-bound tubulin dimers at their flaring ends and alternate between phases of slow growth and rapid shrinkage upon hydrolyzing GTP to GDP – an astounding phenomenon called 'dynamic instability'. Notwithstanding its importance, the mechanism of dynamic instability and microtubule-driven force transduction remains elusive. Mistakes in this process can lead to severe diseases like birth defects, infertility, and tumorigenesis. Therefore, a necessary step prior to developing any new treatments is to answer a basic question: How do microtubules generate forces through directed assembly and disassembly? To this end, we used atomistic, explicit-solvent simulations to scrutinize the microsecond dynamics of complete GTP- and GDP-microtubule models. Our findings have shown that post-hydrolysis microtubules are exposed to higher activation energy barriers for straight lattice formation, which strongly reduces their probability to elongate. We further developed a minimal coarse-grained model of microtubule dynamics and parametrized it using free-energy matching with extensive all-atom simulations of tubulin oligomers and whole microtubules. Our model (1) reconciles previous contradictory measurements of microtubule forces; (2) demonstrates the importance of the spring-like elasticity of and interactions between curling tubulin oligomers at the microtubule end; (3) and shows that the flare microtubule end structure enables proper kinetochore-microtubule attachment in a hydrolysis-state dependent manner. Lastly, future perspectives of my research in the context of the mechanobiology of dynamic biological polymers will be elucidated. In particular, combining data-driven computational tools with state-of-the-art single-molecule, structural, and biochemical

Venue: MSI Small Lecture Theatre, SLS

Abstract: 

Following fertilization, the totipotency is gradually decreased during cleavage divisions until reaching a pluripotent or differentiated state. During this process, transcription factors (TFs) play crucial roles in successful pre-implantation development. Notably, specialized TFs, called pioneer transcription factors (pTFs) have the unique ability to modulate epigenetic and chromatin states by recruiting chromatin remodelers and histone modifiers. Mammalian embryos are initially awakened during zygotic genome activation (ZGA) and further develop into blastocysts including three cell lineages. However, how pTFs/TFs control transcriptional regulation to achieve proper pre-implantation development is largely unknown.

The Orphan nuclear receptor Nr5a2 is expressed in murine embryos, but its function during pre-implantation development is unknown. Leveraging the low-input genomic approach, we discovered that Nr5a2 functions as a pTF that opens the chromatin during ZGA in mouse embryos (Gassler*, Kobayashi* et al., Science, 2022). The cryo-electron microscopy structure of the human NR5A2-nucleosome complex revealed its pioneering activity via minor groove anchor competition (Kobayashi et al., bioRxiv, 2023). We recently found that the chromatin binding of Nr5a2 is dynamically changed during the totipotency-to-pluripotency transition. Interestingly, Nr5a2 co-occupies regulatory elements with some lineage-determining factors at the morula stage (Kobayashi et al., in preparation). Taken together, my work provides insights into how pTFs regulate transcriptional and epigenetic states in mammalian embryos.

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Host: Prof Liz Miller

Venue: MSI, Small Lecture, SLS

Abstract:

 Abnormal assemblies of TDP-43 in neurons and glia are the pathological hallmark of amyotrophic lateral sclerosis (ALS) and multiple types of frontotemporal lobar degeneration (FTLD). Mutations in the TDP-43 gene, TARDBP, can cause ALS and FTLD, and the temporospatial accumulation of TDP-43 assemblies correlates with neurodegeneration, indicating a causative role for TDP-43 assembly in disease. TDP-43 assemblies are also common co-pathologies in other diseases, including Alzheimer's, Parkinson's and Huntington's. The structural and molecular mechanisms of TDP-43 assembly in disease are poorly understood. We developed a protocol to isolate assembled TDP-43 from the brains of patients with ALS and FTLD and determined their structures using cryo-electron microscopy (cryo-EM). We found that TDP-43 assembles into amyloid filaments in these diseases. The ordered filament cores are comprised of the first half of the TDP-43 low-complexity domain and adopt distinct filament folds in different neurodegenerative conditions. These brain-derived filament folds show no similarity to TDP-43 filament folds formed in vitro. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and mono-methylation of R293, and suggest that they may facilitate filament formation and observed structural variation within individual filaments. The structures of TDP-43 amyloid filaments from ALS and FTLD guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies