ERC FUNDED PROJECTS

The evolution from a stem cell to differentiated progeny underpins tissue development and homeostasis, which are driven by a multitude of cell fate choices. The transitions underlying these choices are not well understood. There are a number of challenges that must be overcome to achieve this understanding. In the proposed research we will tackle two of the challenges: first, the dynamics of fate choices, i.e. the dependence of transitions on time and inductive signals, remains cryptic; second, mechanical signalling regulates instructive cues for transitions but its role in the process is uncertain. One of the primary reasons these important aspects of cell fate choice remain a mystery is because the biology has not been coupled to the biotechnology appropriate to unravel it. This is the purpose of the proposed research: we will develop tools based in microfluidics, microfabrication and hydrogels and integrate them with our stem cell biology expertise to illuminate the process of cell fate choice. We will develop single cell microfluidic technology that possesses unprecedented temporal resolution and control over the signalling environment to study cell fate dynamics. We will also synthesize hydrogel substrates to exert complete control over the mechanical microenvironment of stem cells. Finally, we will advance tools to apply reproducible and defined forces to cells in order to study the role mechanical signalling in cell fate choice. Developing the proposed technology kit hand-in-hand with its biological applications will allow us to delve into the mechanisms of biological transitions in multiple stem cell systems, allowing us to uncover universal phenomena governing cell fate choice.

1 876 618 €

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

All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time. Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.

1 899 549 €

Start date: 2015-09-01, End date: 2022-02-28

Visual perception is central to how we think and behave. However, there are major unresolved issues in understanding how the human mind draws on experience to perceive the dynamic and variable world. The COLOURMIND project, led by Franklin, will tackle these crucial issues with an ambitious investigation of the impact of the visual environment on colour perception that will provide a new theoretical framework for the field. The project will ask ground-breaking questions: What aspects of colour perception are affected by the visual environment, such that people from different environments perceive colour differently?; What processes enable colour perception to calibrate to visual experience and what is their nature and scope?; Does colour perception ‘tune-in’ to the visual input experienced during infancy? COLOURMIND will adopt a diverse range of innovative methods to address these questions, and will: i.) investigate the colour perception of people immersed in natural non-industrialised environments in some of the remotest parts of the world to identify the extent to which visual environment shapes colour perception; ii.) use innovative neuroimaging methods to identify how the visual cortex changes in response to chromatic experience; iii.) pioneer the use of ‘Altered-Reality' (next generation virtual reality) to elucidate calibrative processes in colour perception; and iv.) conduct carefully controlled experiments with infants to address the role of development. The cutting-edge questions, innovative approaches and theoretical power of the COLOURMIND project will lead to breakthroughs on issues that are fundamental to understanding the complexity of the human mind (e.g., learning, plasticity and inference; perceptual development; cultural relativity), and findings will have practical application. Overall, the ambitious project will push the frontiers of multidisciplinary research on colour perception, and will resonate throughout the cognitive and social sciences.

1 999 975 €

Start date: 2018-07-01, End date: 2023-06-30

Urgent action is needed to sustainably intensify global crop production using science-based solutions. Across crops, selection for mutations in cis-regulatory regions of transcription factors has been at the centre of the domestication and breeding process to improve productivity traits. Further efforts to advance towards this goal, however, are hampered in the young polyploid genome of wheat as many genes are present as two or three homoeologous copies with overlapping functions. As a result, recessive variation at single loci is often masked by redundancy with homoeologous copies. This understanding, together with the recent breakthroughs in wheat genomics and gene editing approaches, allow us to now propose an innovative strategy to overcome the perennial problem of functional redundancy in polyploid wheat. The aim of this proposal is to use state-of-the-art genomics to produce a novel framework that defines the cis-regulatory landscape of the polyploid wheat genome. I hypothesise that targeting mutations to cis-regulatory regions of transcription factors will result in dominant alleles within the polyploid context. Through genome editing approaches, I will engineer novel dominant alleles that should result in an unprecedented step change in wheat phenotypic variation, with the potential to improve productivity traits. I will benchmark this novel phenotypic variation with that achieved through recessive loss-of-function mutants in the same transcription factors and their putative downstream genes. Upon completion, I will deliver publicly-accessible germplasm with unique and novel variation that will enhance wheat productivity traits beyond what is traditionally possible. This project paves the way to apply similar approaches to other polyploid crops and will demonstrate the transformational impact of innovative genetic solutions towards addressing food security.

1 999 994 €

Start date: 2020-10-01, End date: 2025-09-30