The developing brain resembles a well-tended garden. Budding neurons sprout bushy extensions; but with time, unneeded extensions are “pruned,” as if by an invisible gardener. Entire segments are eliminated and connections between neurons are erased. Many of the neurons then grow new extensions, which wire up the adult brain with amazing precision.
This fascinating “garden design,” essential for sculpting the mature brain and nervous system, is being investigated in the lab of Dr. Oren Schuldiner, who recently joined the Weizmann faculty. Schuldiner seeks to reveal the molecular mechanisms that govern neuronal remodeling: What commands instruct segments of neuronal extensions (axons) to become fragmented and disappear? How do the axons know exactly at which spot to begin disintegrating? How does the axon begin to regrow? And what roles do various brain cells play in these remodeling processes?
Though it seems wasteful to wire up a developing brain by pruning, the seemingly excessive axonal growth in early development probably serves a purpose – one that scientists have yet to discover. It might, for instance, be simply easier to generate exuberant growth and later refine the brain circuits by trimming branches here and there, rather than immediately generating the correct connectivity. Whatever the reason, axonal pruning is obviously an evolutionary success story: It exists in living beings from worms to mammals, most certainly including humans.
Schuldiner was attracted to research into axonal pruning by the novelty of this important and challenging field. In his new lab in the Institute’s Molecular Cell Biology Department, he investigates this process in fruit flies, which can help clarify brain remodeling in humans. Fruit flies have long been considered an excellent model for genetic studies as they are small, cheap and reach maturity within 10 days. And, since each fly’s life cycle involves major transformations, from a larva to an adult fly, its brain undergoes massive pruning and remodeling.
During his postdoctoral studies at Stanford University, Schuldiner designed an approach that dramatically speeds up the screening of fruit fly genes. In such screening, scientists reveal the function of a gene by creating a mutation and observing its consequences; they then map the location of the mutated gene in the genome. To optimize this process, Schuldiner designed a technique for producing just the kinds of mutations that can be examined by MARCM, the pioneering method for viewing individually mutated neurons in the fruit fly brain that was developed by his postdoctoral supervisor Prof. Liqun Luo. As a result, the time it takes to map a fruit fly gene has been shortened from at least a year to just two days. Schuldiner and colleagues used the approach to create some 2,500 types of fruit fly, each with a unique mutated gene. These mutations, covering about 20% of the fly’s genome, provide researchers worldwide with a valuable resource for investigating individual fly genes.
With the help of this powerful method, Schuldiner identified a dozen genes involved in axonal pruning – about twice the number of all previously known pruning genes. At the Weizmann Institute, he is studying the function of these genes and searching for additional molecules and mechanisms that control the remodeling of the nervous system during development. Employing sophisticated genetic techniques and confocal microscopy, he is able to visualize single nerve cells within a whole brain while creating specific mutations in individual neurons.
One of the genes Schuldiner discovered serves as the first known molecular switch that triggers the regrowth of axons after pruning. He intends to find out whether this gene also triggers regrowth after nerve injury and whether it can be manipulated to help induce such regrowth, with a view to potential future therapies.
Because the fragmentation of axons after injury and in certain pathological conditions –
including Alzheimer’s disease and certain other neurodegenerative disorders – is similar to the fragmentation that occurs during developmental axon pruning, Schuldiner’s research on the developing fruit fly brain
could provide valuable new insights into nerve injury and various diseases of the nervous system.
From Sinai to Rehovot
Born in Tel Aviv, Israel, Dr. Oren Schuldiner conducted his undergraduate and graduate studies at the Hebrew University of Jerusalem. After earning a Ph.D. in genetics in 2002, he performed postgraduate research at Stanford University for five years. He joined the Weizmann faculty as a senior scientist in 2008. Schuldiner is married to Maya, a senior scientist in Weizmann’s Molecular Genetics Department, and has two sons: Daniel, seven, and Noam, four. While a student, he worked as a tour guide in Sinai and later wrote and edited the life science column in the Hebrew-language popular science monthly Galileo.
He enjoys hiking, mostly in the desert, as well as scuba diving, photographing people and scenery, and listening to jazz.
Dr. Oren Schuldiner’s research is supported by the Women’s Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women’s Health Research Endowment and the Oprah Winfrey Biomedical Research Fund; the Adelis Foundation; and the estate of Lela London.