Mechanically Induced Gene Regulatory Networks Driving Neural Crest Lineage Switching

About the project

About the Project A 2027 Crick-University College London Joint PhD project with James Briscoe (Crick) and Roberto Mayor (UCL). Please note: to apply to this project, candidates must be eligible for home tuition fee status. Project background and description Neural crest cells (NCCs) are a highly migratory and multipotent embryonic cell population whose behaviour has often been likened to malignant invasion. They can give rise to an exceptionally wide range of cell types, including melanocytes in the skin; neurons and glia in the nervous system; muscle and cartilage cells in the craniofacial region, among many others, thereby contributing to the development of multiple organs and systems. However, the mechanisms underlying this remarkable differentiation potential remain largely unknown. NCCs exhibit striking developmental plasticity, with one of the earliest fate decisions involving the choice between neurogenic and mesenchymal states. How NCCs make this decision is still unclear. Work from the laboratory of Roberto Mayor has established the importance of cell migration, epithelial-to-mesenchymal transition (EMT), and collective behaviour in NCC development [1-3], while James Briscoe has pioneered quantitative approaches to gene regulatory networks (GRNs) and cell fate decisions [4, 5]. Preliminary data demonstrate that mechanical confinement biases NCC fate, shifting gene expression from a neurogenic programme toward a mesenchymal lineage. This suggests that mechanical inputs act upstream of transcriptional regulatory networks, priming lineage commitment. However, the mechanotransductive GRN responsible for this lineage switch remains unknown. Central hypothesis Mechanical confinement activates a specific gene regulatory network that reprogrammes neural crest cells from a neurogenic to a mesenchymal state, integrating mechanotransduction pathways with lineage-specific transcription factors. Aims Aim 1: Define the transcriptional response to mechanical confinement Perform single-cell RNA sequencing (scRNA-seq and scATC-seq) on NCCs under confined versus unconfined conditions to generate a high-resolution map of the transcriptional landscape underlying the lineage switch. Aim 2: Reconstruct the mechanics-induced gene regulatory network Use GRN inference tools, pseudotime analysis, and RNA velocity to predict a regulatory network linking mechanical input to lineage output. Aim 3: Functionally validate the GRN in NCC fate transitions Perform loss-of-function experiments targeting key nodes within the GRN and analyse their effects on both network dynamics and mechanically induced NCC differentiation. Aims 1 and 2 will be carried out using pluripotent human stem cells differentiated into neural crest cells (hiNCs), while Aim 3 will be performed in both hiNCs and Xenopus embryos for in vivo validation. The results of this project will establish a general framework for the mechanoregulation of cell fate. This will provide fundamental insight into developmental decision-making and will also be highly relevant to cancer metastasis (EMT-like transitions), tissue engineering, and regenerative medicine. Candidate background This project is aimed at highly motivated candidates with a strong interest in the biology of cell differentiation and the mechanisms by which cell fate decisions are regulated through the interplay of molecular and mechanical cues. It would suit applicants with a broad background in biological sciences, such as developmental biology, cell biology, genetics, or related disciplines. We particularly welcome candidates who are curious about how gene regulation and physical forces integrate to shape cellular behaviour during development. While prior experience in computational methods or programming (e.g. R, Python, or bioinformatics) would be advantageous, it is not essential, as full training in relevant techniques will be provided during the PhD. Experience with experimental approaches such as cell culture, imaging, or molecular biology would be beneficial, but is not required. Above all, we are seeking candidates who are enthusiastic, willing to learn new interdisciplinary methods, and excited to work at the interface of experimental and computational biology within a collaborative research environment. Lab-specific question Looking at the research undertaken in our labs, what aspect would you be most interested in exploring further? Drawing on your own research experience, what perspective, skill or approach would you bring to investigating it?

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