Research / Clinical Summary

Jim Wilhelm, PhD Assistant Professor, Biological Sciences Cancer Biology Program Contact by Email Visit the Website

While a great deal is known about how proteins are sorted to various membrane bound compartments, very little is known about how proteins are sorted to particular domains within the cytoplasm.

One mechanism for localizing cytoplasmic proteins is to transport the mRNA encoding the protein to the desired location, so that the synthesis of the protein is spatially restricted to particular cytoplasmic regions. Establishment of these domains is further enhanced by a translational control mechanism that ensures that only the properly targeted messages are translated.

This sorting mechanism has been implicated in processes as diverse as stem cell differentiation, regulating synaptic strength in neurons and embryonic pattern formation – underscoring the importance of understanding mRNA localization for medicine, neuroscience, and developmental biology. While the importance of this method of sorting cytoplasmic proteins is clear, it is unclear how localized messages are targeted to different domains or how many cellular or developmental processes utilize mRNA localization.

Dr. Wilhelm's lab utilizes a combination of genetics, biochemistry, and video microscopy to study mRNA localization events in Drosophila melanogaster. Recently, they have biochemically purified a novel component of the RNA localization complex, Trailer hitch (Tral). Surprisingly, tral mutants in both C. elegans and Drosophila have defects in cytokinesis and cellularization. They were able to reconcile these observations when we discovered that the Tral complex is present on subdomains of the endoplasmic reticulum (ER) that border ER exit sites - the sites where ER to Golgi trafficking takes place. Furthermore, tral is required for normal ER exit site formation and is associated with the mRNAs for ER exit site components.

These findings suggest that mRNA localization plays a role in assembling ER exit sites and that the disruption of normal ER exit site assembly can have serious effects on cytokinesis. Since mutations in tral can have dominant effects on cellularization, we are currently exploring if tral could represent a novel class of cancer susceptibility gene.

They are also using a whole genome microarray screen to identify all of the Tral-associated mRNAs and to determine their subcellular locations. This approach will help to better define how Tral function is connected to both ER function and the completion of cytokinesis and will also identify novel roles for mRNA localization in regulating cell division and differentiation.

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