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The nucleus, the largest and stiffest organelle in the cell, is surrounded by a bilayered nuclear envelope that functions as both a structural boundary and as a dynamic hub for integrating signals from the extracellular matrix (ECM) and cytoskeleton to regulate gene expression and cell fate in a process called mechanotransduction. Central to this process is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, composed of SUN-domain proteins (SUN1/2) and KASH-domain proteins (nesprins), which physically couple the cytoskeleton to the nuclear lamina. This PhD project will investigate how the LINC complex governs epidermal stem cell homeostasis and differentiation through mechanical signalling.
Using an inducible SUN1/2 double knockout (dKO) mouse model, we have uncovered striking phenotypes in embryonic skin, including disrupted nuclear morphology, cytoskeletal disassembly, mitochondrial abnormalities, and premature epidermal differentiation coupled with abnormal development of epidermal appendages. These findings suggest that the LINC complex is essential for maintaining nuclear-cytoskeletal integrity and coordinating mechanical cues with transcriptional programs during skin development.
The student will build on this foundation to explore the mechanistic basis of LINC-mediated nuclear mechanosensing in epidermal stem cells. The project will combine in vivo analysis of embryonic and postnatal skin with in vitro studies using primary keratinocytes. The student will receive training in advanced imaging, mouse genetics, transcriptomics, and mechanobiology.
Candidate Requirements
We are seeking a highly motivated and detail-oriented student with a strong interest in nuclear mechanotransduction, stem cell biology, or epithelial development. The ideal candidate will have:
- A first-class or upper second-class degree (or equivalent) in a relevant field such as cell biology, developmental biology, biomedical sciences, or biophysics.
- Prior laboratory experience in molecular biology, imaging, or cell culture.
- A solid understanding of cytoskeletal dynamics, nuclear architecture, or stem cell regulation.
- A willingness to work with animal models, including mouse handling, genotyping, and tissue analysis (training will be provided).
- Strong analytical skills and an interest in learning transcriptomic, metabolomic or biophysical techniques.
- Experience with microscopy, FACs image analysis, or RNA-seq is desirable but not essential.
This project offers a unique opportunity to explore how mechanical forces shape stem cell behaviour and tissue architecture, with implications for understanding developmental disorders, skin diseases, and cancer metastasis. The successful candidate will be encouraged to present their work at international conferences and contribute to high-impact publications.
Project start date: 1 October 2025
