Fly brains provide new insights into the growth and development of human nerve cells

March 27, 2002

An international research team has identified the specific genes that control the growth and development of brain cells in fruit flies. The discovery could have applications well beyond the insect world, providing new insights into human nerve cell development and the treatment of neurological diseases in people.

Scientists from Stanford and the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, report their findings in the March 28 issue of the journal, Nature. In a companion paper, the authors demonstrate how the same genes that control nerve cell growth also affect embryo development in fruit flies.

Rac genes

The Nature studies focus on Rac genes, which are found in the DNA of all animals as well as people. In fact, Rac genes produce a class of proteins called Rac GTPases, whose molecular structure is virtually identical in a wide range of organisms - from fruit flies to humans.

Rac GTPases long have been suspected to play a role in brain development, notes Liqun Luo, assistant professor of biological sciences at Stanford and co-author of the two Nature papers.

"In our study, we unequivocally demonstrate the importance of Rac GTPases in the growth, guidance and branching of axons - fibrous extensions that nerve cells send out to make connections with other nerve cells," says Luo, who also serves on Stanford's Neurosciences faculty.

While fruit flies may seem like simple organisms, Luo points out that a typical fruit fly brain is an extraordinarily complex organ consisting of an intricate network of some 100,000 neurons. For the brain to be wired properly, each neuron must grow, bend and branch in a specific location and direction.

Neuroscientists have determined that neuronal growth, guidance and branching occur in discrete steps. During the growth phase, the neuron sends out an axon, which conducts messages away from the cell, and several dendrites, which carry impulses back to the cell body.

"Once this neuronal polarity is established," Luo writes, " the axon navigates through a complex environment to find its target, and dendrites can undergo extensive growth and branching."

"Mushroom bodies"

Earlier studies suggested that the three Rac genes in fruit flies - called Rac1, Rac2, and Mtl - somehow were involved in regulating axon growth and development. Because these genes regulate a wide variety of other cells besides neurons, their affect on individual brain cells proved difficult to observe. But in the Nature study, researchers successfully used a technique developed in Luo's Stanford lab to target Rac genes in a few-hundred brain cells, while keeping the rest of the fly's DNA intact.

"We knocked the genes out in a small population of isolated neurons," Luo says. "That way we could analyze their function at a very fine resolution, down to a single brain cell."

The researchers focused their attention on the "mushroom body" - a mushroom-shaped cluster of 5,000 neurons, which is the center of memory and learning in insect brains. By eliminating the Rac1, Rac2 and Mtl- genes separately and in combination, Luo and his colleagues were able to control the amount of Rac GTPase protein produced in individual neurons. The results were surprising.

"It turned out that, the more Rac genes we knocked out, the worse the effect," Luo observes. "When we progressively reduced Rac activity in the mushroom body neurons, defects occurred - first in axon branching, followed by guidance and lastly growth."

These results indicate that brain cells need large amounts of Rac GTPase protein to branch properly, not quite so much for proper turning and relatively little for growth, Luo explains.

"The three Rac genes don't contribute equally," adds Stanford postdoctoral fellow Julian Ng, lead author of the Nature study. "Rac1 contributed significantly, Mtl a little bit and Rac2 even less. Previous studies have focused on individual Rac genes, but now it appears that all three genes function synergistically."

According to Ng, these findings suggest that the brain is really a "community of neurons," where defective cells and healthy cells interact to make "collective decisions."

Learning, memory and disease

These findings may have important applications for medical research in humans, Luo points out, noting that the ability of adult neurons to change shape and branching - a property known as "structural plasticity" - is considered essential to memory and learning in people. Genes that regulate neuronal growth, guidance and branching during development could be reused in adult brains for structural plasticity, Luo maintains.

"Hence, these studies in mushroom body neurons of fruit flies could help us understand the mechanisms of structural change that underlie learning and memory in human brains -- and may open up new avenues of research into regeneration of damaged or diseased neurons," he adds. "Many human genetic diseases result from mutations in genes that regulate Rac signaling," Luo continues.

Therefore, understanding how Rac genes affect neuronal growth and development might lead to preventative treatments for William's syndrome, nonsyndromic X-linked mental retardation and other inherited brain disorders, he concludes.

Other co-authors of the Nature study, titled "Rac GTPases control axon growth, guidance and branching," are former Stanford research assistants Timothy Nardine and Matthew Harms; undergraduate Julia Tzu; and Ph.D. candidate Ann Goldstein. Co-authors from IMP, a division of the Boehringer Ingelheim company, are Yan Sun, George Dietzl and Barry J. Dickson.
-end-
The companion study in Nature on the effect of Rac genes on developing fruit fly embryos is co-authored by Ng, Tzu, Dietzl, Sun, Harms, Nardine, Luo and Dickson. The lead author of the embryo study is Satoko Hakeda-Suzuki of IMP.

The research was supported by grants from the National Institutes of Health, the Human Frontiers Science Program, the American Cancer Society California Division and Boehringer Ingelheim GmbH.

CONTACT: Mark Shwartz, News Service, (650) 723-9296, mshwartz@stanford.edu

COMMENT: Liqun Luo, Biological Sciences, (650) 723-6645, lluo@stanford.edu
Julian Ng, Biological Sciences, (650) 725-5809, julianng@stanford.edu

EDITORS: Luo and Ng's studies on fruit fly development and growth will be published in the March 28 issue of Nature. Images of fly brains will be available at http://newsphotos.stanford.edu (slug: "Fly Brains").

Relevant Web URLs:
http://www-leland.stanford.edu/group/luolab/
http://www.molbio.princeton.edu/labs/tsien/Publications/GeneticAnalysis.pdf
http://www-med.stanford.edu/sbrc/
http://www.imp.univie.ac.at/

-By Mark Shwartz-

Stanford University

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.