ERC FUNDED PROJECTS

Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.

2 000 000 €

Start date: 2017-01-01, End date: 2022-12-31

During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.

2 323 468 €

Start date: 2016-07-01, End date: 2021-06-30

Cooperation represents an evolutionary puzzle because natural sCooperation poses an evolutionary problem because natural selection is thought to favour cheaters over co-operators. However, theory and studies in humans show us that co-operators are preferred over cheaters as social and sexual partners. Partner choice may therefore provide a powerful explanation for the evolution and stability of cooperation, alongside kin selection and self-serving benefits, but we lack an understanding of its importance in natural systems. Recent studies showing that animals have a preference for associating with more cooperative individuals are promising but were mostly conducted in artificial captive conditions, making the evolutionary implications of partner choice hard to assess. Manipulating cooperation in the wild to test the fitness consequences of partner choice is the leap that is required to understand whether or not partner choice provides an evolutionary explanation for cooperation. I will pursue this goal using a long-term study that I established on a highly cooperative wild bird, the sociable weaver Philetairus socius. New methodological developments now allow us to conduct large-scale experiments in the wild, and detailed tracking of individual for several years will allow us to quantify the fitness consequences of choice. Specifically, here I will: i) use a new conceptual framework to test whether cooperation is repeatable (a pre-requirement for partner choice); ii) use state-of-the-art technology to manipulate cooperative behaviour and measure the resulting patterns of social and sexual partner choice; iii) use physiological measures and lifetime reproductive success to examine the fitness benefits arising from partner choice and the underlying mechanisms for both co-operators and the individuals that associate with them. Ultimately, the project will provide a novel and robust evaluation of the roles of social and sexual selection for the evolution of cooperation.

1 999 335 €

Start date: 2020-06-01, End date: 2025-05-31

You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.

2 000 000 €

Start date: 2018-04-01, End date: 2023-03-31