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A new Klemm Lab-led paper has uncovered a new mechanism involving the endoplasmic reticulum that is critical to the organisation and position of the microtubule (MT) cytoskeleton, which ultimately dictates the shape and function of our body’s cells.

Genetic perturbation of ER (green) dynamics in COS7 cells causes tightly packed microtubule (red) bundles.

The microtubule (MT) cytoskeleton gives the eukaryotic cells of the body their shape, helps organise the cell’s parts, and provides a basis for movement and cell division. Yet, the basic principles regulating the position of MTs in interphase cells before cell division takes place are largely unknown.

The endoplasmic reticulum (ER), which constitutes more than half of the membranous content of a cell, has long been known to produce and transport proteins for the rest of the cell to function. However, a new paper led by Associate Professor Robin Klemm and first authored by Dr Maria S. Tikhomirova, has uncovered an unexpected role for the ER in controlling the organisation of the MT cytoskeleton in the cell. According to Prof Klemm: “This new perspective on the role of the ER in cellular organisation opens up a number of research directions and will lead to better understanding of mechanisms that cells use to position the MT cytoskeleton during migration or initiation and maintenance of axons.”

Using cutting edge computer simulation and automated microscopy, researchers have found that the dynamics of the ER network is pivotal in directing the sub-cellular distribution of MTs. In particular, they discovered that inhibition of membrane fusion in the ER leads to dramatic changes in ER network dynamics, namely strong re-positioning of both the ER membranes and the MT-cytoskeleton within cells.

In collaboration with computational scientists in the Shemesh laboratory at the Technion - Israel Institute of Technology, the team uncovered that the local density of ER tubule connections are at the core of a new mechanism generating a net pulling force that acts on MTs during interphase. In normal conditions, ER-connections rapidly equilibrate across the entire cell by releasing and forming new ER-network junctions at fast pace. In ER-fusion deficient cells, this process is too slow, rendering the whole MT-ER system unstable. This instability leads to the formation of MT bundles, an abnormality in cells that may have implications in the context of disease.

Mutations in the ER fusogens called Atlastins are known to cause neurodegenerative diseases such as hereditary spastic paraplegia, a group of inherited disorders that causes weakness and stiffness in the leg muscles, due to atrophy in the long axons of motor neurons, that gradually worsens over time. Prof Klemm said: “We will now continue to investigate whether the basic mechanisms we have newly revealed are disease relevant and form part of the explanations for the axonal instability observed in this group of axonopathies.”

The new paper “A role for endoplasmic reticulum dynamics in the cellular distribution of microtubules”, available to read in PNAS, is a collaboration between the Klemm Lab at DPAG, University of Oxford and the Shemesh group at the Federal Institute of Technology in Haifa, Israel.

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