Worm ‘menorahs’ may repair brains

Israel-US study finds how gene “sculpts” neurons.

By JUDY SIEGEL-ITZKOVICH
microscopic worm 311 (photo credit: Technion)
microscopic worm 311
(photo credit: Technion)
Israeli and American researchers have discovered how a gene “sculpts” neurons into a menorah-like shape in the nervous system of a transparent, millimeter-long worm. The finding, called a “breakthrough” by the scientists and published in the online version of the journal Science (Science Express), could eventually have far-reaching implications for the rehabilitation of people with central nervous system (brain and spinal cord) damage.
The article, esoterically titled “The Fosogen EFF-1 Controls Sculpting of Mechanosensory Dendrites,” was written by doctoral student Meital Oren-Suissa of the Technion-Israel Institute of Technology, Dr. David Hall of the Albert Einstein College of Medicine in New York, Dr. Millet Treinin of the Hebrew University-Hadassah Medical School, Prof. Gidon Shemer and Prof. Benjamin Podbilewicz, both of the Technion.
While biologists have known for years that many neurons form complicated tree-like structures, it was not known how the neurons did so and maintained them. To unravel this mystery, Podbilewicz and colleagues first studied the dynamic development of two neurons (called PVDs) required for reception of strong mechanical stimuli in the roundworm known well to scientists – Caenorhabditis elegans (C. elegans).
C. elegans, a free-living, transparent nematode that lives in the soil and feeds on bacteria, looks insignificant, but it is so popular as a model organism for research that four Nobel Prizes connected to research involving it have been awarded in the last four decades – the last three since 2002.
The reasons for this are that it has only 302 neurons; it can be bred cheaply and frozen and defrosted without being killed; it can be “seen through” and have its processes monitored; it’s the first multicellular organism to have its genome completely sequenced; it can have the functions of specific genes interrupted; and it can serve as a model for nicotine dependence. A veritable gold mine in the study of neurons, the worm has been used in many other fields of biology, including the study of how organs form, how embryos develop, aging and apoptosis (programmed cell death).
Prof. Martin Chalfie of Columbia University, who shared the 2008 Nobel Prize in Chemistry, previously showed that when the worm’s body was hit, it responded by moving away, demonstrating that the PVDs were necessary for C. elegans to sense pain.
The PVDs have “elaborate neuronal trees comprising structural units that [Jews] call menorahs, because they look like multi-branched candelabra,” said Podbilewicz, adding that each of these tiny branches is just one-millionth of an inch in diameter. Using light and electron microscopy in live and preserved worms, the team also studied how the number, structure and function of these menorahs were maintained. This candelabrum-like neuron structure has not been seen in other creatures.
The team discovered that a membrane protein called EFF-1 (which is also essential for the mediation of fusion between cells to form giant cells with multiple nuclei) has important roles in menorah formation and maintenance. EFF-1 also acts in the PVDs to trim the branches of neuronal tree menorahs. When the gene encoding for EFF-1 was deleted by Oren-Suissa, Shemer and Podbilewicz, the worm showed disorganized menorahs with many more branches. Oren-Suissa, who did her doctoral work on C. elegans, showed that too much EFF-1 in the PVD reduced branching. By cutting, retracting and fusing branches, EFF-1 prunes excess or abnormal branches, serving as part of a quality control process that is important for the sculpting and maintenance of complicated menorahs.
“When we looked at the mutations [worms without this gene], we found that they lack menorahs but have a big mess in the branches,” said Podbilewicz. “From this, we reached the conclusion that this gene is responsible for the building of the menorahs as a sculptor and designer, and we were left to study how it did this.”
The team displayed the images through sophisticated microscopes andfound that the movement in the worm was very dynamic. When one branchwas moved for some reason in the “wrong direction,” the worm would“correct it” by pulling it back. To understand this phenomenon, theylooked for proteins that influence the action of pulling. Theyinterfered with the natural process, using a mutation of the EFF-1 genethey discovered 10 years ago as being responsible for melding cellstogether.
It was important to find these genes, the team said, because with theirhelp, it would be possible to find, even in humans, the genesresponsible for building neurons in the human brain. This, theyconcluded, would lead in the future to repairing damage to people’sbrains and spinal cord that caused devastating debilitation. Their workon the formation and maintenance of tree-like nerve cell structurescould also have applications in the treatment of neurodegenerativediseases, as well as the repair of damaged vital nerves.