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Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain—gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation.
In the journal Cell, researchers for the first time describe how faulty wiring occurs when RNA molecules embedded in a growing axon do not degrade following the release of instructions to help steer that axon. What happens, for example, when the signal that tells the axon to turn—which should disappear after the turn is made—remains active, interfering with new signals meant to guide the axon into another direction.
The scientists hope there may be a way to use this new knowledge to fix circuits.
"Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study's senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology.
Dr. Jaffrey: "The brain is quite 'plastic' and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring."
Disorders associated with faulty neural circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others.
In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known—and therefore more prone to error.
Proteins Sense the Environment to Steer the Axon
Dr. Jaffrey: "It is critical that axons are precisely positioned in the spinal cord. If they are improperly positioned and form the wrong connections, signals can be sent to the wrong target cells in the brain."
During brain development, neurons must connect to each other by extending their long axons to touch one another.
Ultimately, fully extended neurons form a circuit between the brain and target tissues through which chemical and electrical signals are relayed. In this study, researchers specifically investigated neurons that travel up the spinal cord into the brain.
The way that an axon guides and finds its proper target is through structures called growth cones located at the tips of axons.
Dr. Jaffrey: "These growth cones have the ability to sense the environment, determine where the targets are and navigate toward those targets. The question has always been -- how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?"
The team found that RNA molecules embedded in the growth cones are responsible for instructing the axon to move left or right, up or down. These RNAs are translated by growth cones into antenna-like proteins that steer the axon much like a self-guided missile.
Dr. Jaffrey: "As a circuit is being built, RNAs in the neuron's growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears.
If these RNA instructions do not disappear when they should, the axon does not position itself properly -- it may go right instead of left -- and the wiring will be incorrect and the circuit faulty."
RNAs Have Tremendous Power Over Brain Development
This research found answers to a long-standing puzzle about brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey's laboratory.
Dr. Colak: "There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, exhibit as spasticity or other movement disorders. That has raised a major question—why would RNA degradation pathways be so critical for properly creating brain circuits?
What we show here is that not only does RNA need to be present in growth cones to give instructions, it also needs to be removed from the growth cones to take away those instructions at the right time. Both these processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation."
"The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn't anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it."
Other authors of the study are Dr. Sheng-Jian from the Department of Pharmacology at Weill Cornell Medical College and Dr. Bo T. Porse from the Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Denmark.
This work was supported by NIH grant NS56306 to Dr. Jaffrey and a European Molecular Biology Organization (EMBO) postdoctoral fellowship to Dr. Colak.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas.
Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.
Original press release: http://weill.cornell.edu/news/releases/wcmc/wcmc_2013/06_06_13.shtml