Spatial Control of Wnt–ERK Signalling by Glypican-Dependent Ligand Dispersal in Development and Disease

About the project

About the Project Project Title : Spatial Control of Wnt–ERK Signalling by Glypican-Dependent Ligand Dispersal in Development and Disease Glypicans are a family of heparan sulfate proteoglycans that regulate extracellular signalling environments during development. Human genetics highlights the importance of this regulation: loss-of-function mutations in GPC6 cause omodysplasia, a rare skeletal dysplasia characterised by impaired growth and developmental defects. More recently, genetic studies have implicated glypicans in neurological disease, with emerging links to disorders including schizophrenia and Parkinson’s disease. Despite these associations, the molecular mechanisms by which glypicans shape signalling outputs in different tissues remain poorly understood. Recent work has identified a conserved role for GPC6 in controlling the extracellular distribution of Wnt ligands. Disruption of this process collapses Wnt gradients and leads to spatially restricted signalling, suggesting that glypicans regulate not only the range but also the intensity of morphogen signalling. We have found that loss of GPC6 function leads to hyperactivation of ERK signalling, through dysregulated non-canonical Wnt pathway activity. This suggests that extracellular control of Wnt ligand distribution can directly influence intracellular signalling output, but the molecular mechanisms linking these processes remain unclear. This project will investigate how glypican-dependent regulation of Wnt signalling is coupled to ERK activation, with a particular focus on identifying the signalling cascade linking extracellular ligand organisation to downstream pathway output. Particular emphasis will be placed on the role of small GTPase-mediated signalling in integrating spatially restricted Wnt signals and modulating intracellular pathway activity. The project will primarily focus on the nervous system, where non-canonical Wnt signalling plays key roles in regulating cell polarity, migration, neurite outgrowth, and neuronal specification. These processes are essential for the formation and maintenance of neural circuits and have been increasingly implicated in neurodevelopmental and neurodegenerative disorders. The student will investigate whether loss of GPC6 leads to dysregulated Wnt–ERK signalling in the developing mouse brain, with a particular focus on dopaminergic neuron specification and patterning. To explore relevance to human disease, the project will use induced pluripotent stem cell (iPSC)-derived neurons and astrocytes to test whether similar signalling mechanisms operate in human cells. A key aspect of the project will be to define the downstream consequences of dysregulated Wnt–ERK signalling in neural cells. Non-canonical Wnt signalling, including Wnt5a-dependent pathways, plays an important role in neuronal maturation, regulating cytoskeletal organisation, neurite development, and synaptic connectivity—processes that intersect with ERK-dependent signalling networks. The student will investigate how perturbation of GPC6 alters these downstream responses, with a particular focus on identifying signalling targets and cellular behaviours that are Wnt-Erk regulated. Understanding these outputs will be important not only for defining core biological mechanisms, but also for improving in vitro models of neuronal differentiation and maturation, ensuring that iPSC-derived neurons faithfully recapitulate relevant developmental signalling states. Together, this project will define how extracellular regulation of morphogen signalling is translated into intracellular pathway activation, providing new mechanistic insight into how disruption of signalling architecture can contribute to developmental defects and neurological disease. This project will be undertaken with BitBio. Principal Supervisor Dr Ian McGough Email address: Ian.McGough@babraham.ac.uk Competition funded studentship (unfunded) – You will need to apply for your own funding, possible sources of funding include the University of Cambridge-wide funding competitions , such as the Gates Cambridge Trust and Cambridge Trust (please visit the University of Cambridge Funding Search webpage). Please ensure you check the postgraduate funding competition box when applying. URL link to personal profile page or website: Ian McGough | Babraham Institute The applications deadline for all PhD studentships: 8 th December 2027 Please note interviews will be held the week commencing 18 th January 2027 Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University. Incomplete applications will not be considered.

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