To the cell’s edge - and back
A radar-like system controls nerve growth
What do nerve cells and driverless cars have in common? Similar to the collision avoidance sensors that emit radar-like “chirps” to calculate the distance between a car’s physical edges and surrounding obstacles, our body’s neurons depend on a steady stream of bi-directional signals to regulate protein biosynthesis and cellular growth.
As a team of Institute researchers recently demonstrated, artificial “tuning” of such signals can cause axons—the appendage of a neuron that carries messages away from the cell body—to grow significantly longer. Their findings may eventually contribute to better treatment of diseases of the nervous system, nerve damage, and cancer.
“How neurons sense and regulate their own size is a fascinating question,” says Prof. Mike Fainzilber, a member of the Department of Biomolecular Sciences. “Neurons exhibit the greatest size differences of any class of cells, ranging from a few microns to more than a meter in large mammals. We want to learn how neurons convey information from one end of the cell to the other.”
So far, they’ve learned a lot. In 2012, Dr. Ida Rishal, a staff scientist in the Fainzilber lab, published a study suggesting that the oscillation of molecular signals could function as a kind of radar detector, revealing cell length by measuring the frequency of arrival of signals to the cell center from axon endings at the cell periphery.
Now, in a study published in Cell Reports in 2016, the team - which included doctoral student Ella Doron-Mandel, Dr. Rishal, and associate researcher Dr. Rotem Ben-Tov Perry—discovered how the messaging begins: with a protein called nucleolin.
“Nucelolin binds to a certain type of mRNA - a genetic template for protein synthesis - creating a complex that travels from the nucleus to the outer edge of the cell,” Dr. Doron-Mandel explains. “Upon arrival, the complex manufactures a protein called importin. This is the protein that cycles back to the cell center, making the neuron aware of its size.”
The compound that made it possible to investigate nucleolin’s function is also what ties this discovery to cancer.“We inhibited nucleolin using an experimental cancer drug,” Doron-Mandel says. “The drug caused the nucleolin-mRNA complex to remain in the cell center, rather than travel to the periphery.” And as she explains, this had implications for cellular size sensing, as well as for growth.
“The drug ‘fooled’ the neuron into thinking it was much shorter than it was,” Doron-Mandel says. “As a result, the neurons grew at up to five times the usual rate. This manipulation also worked on connective tissue cells, which were also made to grow larger than normal.”
The nucleolin-binding drug’s demonstrated ability to disrupt size sensing may eventually contribute to new strategies for slowing cancer progression. Moreover, an in-depth understanding of neuronal growth regulation may lead to technologies designed to promote post-injury nerve regeneration.
The work was carried out in collaboration with research teams associated with the Adelson Program in Neural Repair and Rehabilitation. “We're privileged to be part of this collaborative model for scientific research, which is funded by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation,” Prof. Fainzilber says. “Although the clinical science of nerve repair is still in its infancy, basic research in this direction may yet yield high dividends.”
The kosher connection
And what’s great science without a little serendipity—the kind only found in Israel?
The scientists purified nucleolin from the bovine sciatic nerve, which was readily available because eating the sciatic nerve is prohibited under Jewish religious dietary laws. Kosher slaughterhouses in Israel, such as the one with which they worked (a study co-author is its veterinarian), must remove the sciatic nerve from meat for sale. Says Prof. Fainzilber: “We were happy to take advantage of this expertise to get, literally, buckets of sciatic nerve tissue for analysis.”
Prof. Mike Fainzilber's research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Laraine and Alan A. Fischer Laboratory for Biological Mass Spectometry. He is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience.
Prof. Mike Fainzilber