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The cell-wide web coordinates neuronal stem cell specification and plasticity by directing calcium flux across cytoplasmic nanocourses

College of Medicine and Veterinary Medicine

About the Project

Cells select specific functions by calcium signals, greatly delivered through the sarco/endoplasmic reticulum (S/ER), which runs contiguously from the outer nuclear membrane (ONM) to its plasma membrane (PM) junctions. The consensus is that cell excitability and plasticity are directed by highly localised calcium sparks and/or propagating calcium waves; (2) Gene expression is coordinated by spatiotemporal patterns of propagating calcium waves that enter the nucleoplasm across the nuclear envelope (NE). However, this cannot explain how calcium coordinates the full panoply of cellular processes.
Excitingly, we discovered the “cell-wide web”, a network of cytoplasmic nanocourses spanning from NE to PM. Cytoplasmic “nanocourses” are demarcated by S/ER nanojunctions and strategically positioned, nanocourse-specific calcium pumps and channels. Discrete lines of communication are thus provided, directing site-specific calcium flux across nanoscale path lengths, from release site to targeted signalling complex. Within the cell-wide web NE invaginations demarcate diverse networks of cytoplasmic nanocourses that project deep into the nucleus. Specialised calcium channels are targeted to invagination ONM, through which thus segregated nanocourses receive calcium flux from stores held between ONM and adjacent inner nuclear membrane (INM). Our studies predict that trans ONM calcium flux facilitates cycles of gene expression by adjusting interactions between INM proteins and epigenetic marks segregated by their associated invaginations. The nucleus may thus be informed by environmental cues in a manner analogous to charge conduction by carbon nanotubes, and relay conditional responses through gene expression regulation.
You will test a new research question: Does elaboration of nuclear invagination networks direct neural stem-cell specification and neural plasticity? Supporting this, neither NE invaginations nor the cell wide web are hardwired, but reconfigure to deliver different outputs. It is therefore notable that nuclear invaginations are absent from neural stem-cells yet numerous in primary neurons, where development, action potential firing frequency and age may modulate invagination number, shape and histone association.
To achieve these goals you will use and receive training in: Confocal imaging to examine mechanisms of stimulus- and region-specific ONM calcium flux, and map the composition, positions and distances of separation of nuclear membrane complexes through which ONM calcium flux regulates gene expression; RNA-Seq to assess global changes in gene expression; Bioinformatics.

Funding Notes

You will hold a BSc in Pharmacology, Physiology, Genetics or a related discipline.


Duan J., Navarro-Dorado J., Clark J.H., Kinnear N.P., Meinke P., Schirmer E.C., Evans A.M. (2019). The cell wide web coordinates cellular processes by directing site-specific Ca2+ flux through cytoplasmic nanocourses. Nat Comm 10, 2299, doi:10.1038/s41467-019-10055-w.

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