In this continuing “Five questions with…” series, Sharlini Sankaran talks with Louis-Jan “LJ” Pilaz, Regeneration Next Postdoctoral Fellow from the Silver Lab at Duke, about his recently-published paper in the journal Current Biology.
What excites you about your work?
I have always been fascinated by the brain, this incredibly complex organic machine. The developing brain contains these cool radial glial cells that give rise to our “thinking units”, our neurons. But radial glial cells do so much more. They generate specialized brain cells such as astrocytes. They form a barrier between the brain and the rest of the body during development, and they also serve as a scaffold for migrating neurons.
They can do all this thanks to their unique morphology. Radial glial cells, are absolutely gorgeous and remain full of mysteries. I love to spend time thinking about them and I’m driven by the need to know more about them. Anything impacting their functioning can have devastating impacts on brain development and eventually lead to neurodevelopmental diseases. The more we know about them, the more likely we will be able to find cures for those diseases.
Can you describe the breakthrough discovery that led to the publication of this paper?
Radial glial cells bear two long protrusions, called processes, emanating from their cell body. These processes end with structures called “endfeet” because of the way they look. One of these processes spans the whole brain radially, going from the center outwards. It is called the basal process and ends with basal endfeet tightly connected to the “roof” of the brain. In the mouse the basal process can have a length of several hundred microns, in the human several millimeters. If the basal process is not properly maintained, neurons will not properly migrate to their final destination. If the connection between radial glial endfeet and the roof of the brain is altered, neurons will migrate too far away and will end up outside the brain. Despite the importance of those structures, little is known about what is going on inside them.
In our latest paper, we show that the basal process is a highway for molecular transport. We uncovered some fascinating functions taking place in the basal endfeet: we imaged messenger RNAs being transported at high speed from the cell body to the basal endfeet within living brain tissue (see video). With the help of Ashley Lennox, a graduate student in the lab, we showed that these basal endfeet RNAs can locally produce proteins, far away from the cell body. We discovered 115 different RNAs that accumulate in the basal endfeet. Importantly about 30% of those RNAs have been implicated in neurological diseases and might play a significant role during brain development. We also show that RNA transport may be influenced by FMRP, an RNA-binding protein linked to Fragile X Syndrome, the most common cause of autism caused by a mutation of a single gene.
Why is this discovery important to the field of regenerative medicine?
Neural stem cells receive a lot of attention in the field of regeneration in the nervous system. In some areas of the adult brain, stem cells and progenitors are still proliferating and differentiating. There is hope that one day we will be able to harness those neural stem cells already in place to produce neurons that were lost after a stroke or injury. Another strategy would be to grow neural stem cells in a dish and then introduce them into damaged brains to produce new neurons. Our paper uncovers completely novel mechanisms at play in radial glial cells. This is yet another piece of the neural stem cell “puzzle” that scientists need to consider when attempting either strategy to stimulate regeneration of injured or lost neurons in the brain.
Our paper establishes radial glial cells as a model of choice to study RNA localization and local protein production in distant areas of a cell. These two mechanisms are implicated in the regeneration of axons after injury. For that reason, future studies of RNA localization in radial glial cells may yield findings critical to better understand how it plays a role in the regenerating axon.
What comes next in this research?
Scientists do not know why radial glial cells spend so much energy to transport RNAs across such long distances and what that means for normal brain function. We are now actively trying to uncover the function(s) of those localized RNAs during brain development.
Is there anything else you want to share about your work?
I feel very fortunate to be working in Debby Silver’s lab and to be part of the Duke community. All this work would not have been possible without the support of core facilities and lively discussions with other labs. Duke is an amazing place to do science!
L-J’s work was recently featured in the Duke Med School Blog. You can read more about his discoveries here.