The dedicated gardener

Weizmann Institute scientists are trying to unravel the puzzle of brain cell remodeling

The developing embryonic brain is much like a growing orchard. The growing nerve cells grow branched branches, but over time, as if by an invisible gardener, the unnecessary branches are "pruned", and many connections between the nerve cells are deleted. Some of the cells then grow new branches, which network the adult brain with incredible precision.
This fascinating "pruning" process, which is essential for determining the shape and function of the adult brain, was studied in the laboratory of Dr. Oren Shuldiner, who recently joined the Department of Molecular Biology of the Cell at the Weizmann Institute of Science. Dr. Shuldiner aims to discover the molecular mechanisms that control the design of the "landscape" of the nerve cells (neurons): what are the processes and molecules that cause parts of the axons - the long extensions of the neurons - to disintegrate and disappear? How does the axon know exactly at what point to start the disassembly? How does the axon begin to regrow? And what roles do the different cells in the brain play in these processes? The way the brain shapes itself,
Through pruning, may seem wasteful at first glance. But quite a few scientists believe that the seemingly unrestrained growth of axons plays a central role in embryonic development. It is possible, for example, that it is easier to grow many branches - which will ensure the creation of an excess of intercellular connections, beyond those necessary for brain activation - and then trim the unnecessary connections and precisely design the brain circuits necessary for its activity.

The possible alternative to this mechanism is to build precise circuits from the start - a process that requires very complex control mechanisms. Either way, axon pruning is clearly an evolutionary success story. Therefore, it exists in a wide variety of living creatures, from worms to mammals, and it is very likely that it also exists in humans. Dr. Shuldiner studies the process of axon pruning in fruit flies, which are known as a suitable model for developmental-genetic studies. Beyond their convenient size and their short generation time, fruit flies are particularly useful in the study of remodeling processes in the nervous system thanks to the great changes they go through in their lives - caterpillar to pupa and pupa to adult fly - which involve significant processes of pruning and remodeling of the brain.

In the post-doctoral research he carried out in the group of Prof. Liqun Luo from Stanford University, Dr. Shuldiner developed a method that greatly speeds up the genetic scanning of fruit flies. Scans of this type are designed to find out the role of a certain gene by creating a mutation in the gene, and checking the results of the mutation. In the next step, the scientists map the location of the tested gene in the genome. To study processes in the development of the nervous system, Dr. Schuldiner used a unique method developed by Prof. Lou, called MARCM, which allows mutations to be created in individual nerve cells and to examine their "pruning" process in the entire brain. Dr. Schuldiner developed a method that allows for the random generation of mutations that are adapted to MARCM and can be rapidly mapped.

This is how the fruit fly garden mapping process, which until then lasted about a year, was shortened to just two days. With these means, Dr. Schuldiner and his research partners produced about 2,500 types of mutant flies. This database, which covers about a fifth of the fly genome, provides a powerful research tool for scientists all over the world who are involved in the genetics of fruit flies. So far, Dr. Schuldiner has been able to locate about ten genes involved in axon pruning mechanisms - about half of the known number of genes. At the Weizmann Institute of Science he plans to investigate the exact role of these genes. For example, one of the genes he discovered serves as a primary molecular switch, which causes regrowth of axons after pruning. Dr. Shuldiner intends to find out whether this gene also causes the regrowth of axons after a nerve injury, and whether it can be activated to cause such growth for possible future treatments. In light of the great similarity between the natural pruning processes in the fly's brain and the breaking of axons that occurs as a result of degenerative brain diseases or following a brain injury, it is possible that his research will provide new insights into the nature of the damage and ways to repair it.