Scientists describe the genetic signature of a vital set of neurons

November 29, 2012

Scientists at NYU Langone Medical Center have identified two genes involved in establishing the neuronal circuits required for breathing. They report their findings in a study published in the December issue of Nature Neuroscience. The discovery, featured on the journal's cover, could help advance treatments for spinal cord injuries and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), which gradually kill neurons that control the movement of muscles needed to breathe, move, and eat.

The study identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC). These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are "probably the most important motor neurons in your body," says Jeremy Dasen, PhD, assistant professor of physiology and neuroscience and a member of the Howard Hughes Medical Institute, who led the three-year study with Polyxeni Philippidou, PhD, a postdoctoral fellow.

Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus.

The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing. "We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival," Dr. Dasen says. Degeneration of PMC neurons is the primary cause of death in patients with ALS and spinal cord injuries.

To find out what distinguishes PMC neurons from their spinal neighbors in mice, Dr. Philippidou injected a retrograde fluorescent tracer into the phrenic nerve, which wires the PMC to the diaphragm, and then looked for the spinal neurons that lit up as the tracer worked its way back to the PMC. He used transgenic mice that express green fluorescent protein (GFP) in motor neurons and their axons in order to see the phrenic nerve. After noting the characteristic gene expression pattern of these PMC neurons, Dr. Philippidou began to determine their specific roles. Ultimately, a complicated strain of transgenic mice, based partly on mice supplied by collaborator Lucie Jeannotte, PhD, at the University of Laval in Quebec, revealed two genes, Hoxa5 and Hoxc5, as the prime controllers of proper PMC development. Hox genes (39 are expressed in humans) are well known as master gene regulators of animal development.

When Hoxa5 and Hoxc5 are silenced in embryonic motor neurons in mice, the scientists reported, the PMC fails to form its usual, tightly columnar organization and doesn't connect correctly to the diaphragm, leaving a newborn animal unable to breathe. "Even if you delete these genes late in fetal development, the PMC neuron population drops and the phrenic nerve doesn't form enough branches on diaphragm muscles," Dr. Dasen says.

Dr. Dasen plans to use the findings to help understand the wider circuitry of breathing--including rhythm-generating neurons in the brain stem, which are in turn responsive to carbon dioxide levels, stress, and other environmental factors. "Now that we know something about PMC cells, we can work our way through the broader circuit, to try to figure out how all those connections are established," he says.

"Once we understand how the respiratory network is wired we can begin to develop novel treatment options for breathing disorders such as sleep apneas," adds Dr. Philippidou.

In late October Dr. Dasen lost many of his transgenic mice when Hurricane Sandy flooded the basement of the Smilow building at NYU Langone Medical Center. But just before the hurricane hit, he sent an important group of these mice back to Dr. Jeannotte in Quebec, "so we didn't lose everything," he says.
-end-
A commentary about the study appears in the issue at http://www.nature.com/neuro/journal/v15/n12/full/nn.3272.html

About NYU Langone Medical Center

NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one of the nation's premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals - Tisch Hospital, its flagship acute care facility; the Hospital for Joint Diseases, recognized as one of the nation's leading hospitals dedicated to orthopaedics and rheumatology; Hassenfeld Pediatric Center, a comprehensive pediatric hospital supporting a full array of children's health services; and Rusk Institute of Rehabilitation Medicine, the world's first university-affiliated facility devoted entirely to rehabilitation medicine - plus NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center's tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research. For more information, go to www.NYULMC.org.

NYU Langone Medical Center / New York University School of Medicine

Related Spinal Cord Articles from Brightsurf:

Stem cells can help repair spinal cord after injury
Spinal cord injury often leads to permanent functional impairment. In a new study published in the journal Science researchers at Karolinska Institutet in Sweden show that it is possible to stimulate stem cells in the mouse spinal cord to form large amounts of new oligodendrocytes, cells that are essential to the ability of neurons to transmit signals, and thus to help repair the spinal cord after injury.

Improving treatment of spinal cord injuries
A group led by UC Riverside bioengineering professor Victor G.

Spinal cord gives bio-bots walking rhythm
Miniature biological robots are making greater strides than ever, thanks to the spinal cord directing their steps.

Co-delivery of IL-10 and NT-3 to enhance spinal cord injury repair
Spinal cord injury (SCI) creates a complex microenvironment that is not conducive to repair; growth factors are in short supply, whereas factors that inhibit regeneration are plentiful.

Locomotor engine in the spinal cord revealed
Researchers at Karolinska Institutet in Sweden have revealed a new principle of organization which explains how locomotion is coordinated in vertebrates akin to an engine with three gears.

Neurological signals from the spinal cord surprise scientists
With a study of the network between nerve and muscle cells in turtles, researchers from the University of Copenhagen have gained new insight into the way in which movements are generated and maintained.

An 'EpiPen' for spinal cord injuries
An injection of nanoparticles can prevent the body's immune system from overreacting to trauma, potentially preventing some spinal cord injuries from resulting in paralysis.

From spinal cord injury to recovery
Spinal cord injury disconnects communication between the brain and the spinal cord, disrupting control over part of the body.

Transplanting adult spinal cord tissues: A new strategy of repair spinal cord injury
Spinal cord injury repair is one of the most challenging medical problems, and no effective therapeutic methods has been developed.

Gene medication to help treat spinal cord injuries
The two-gene medication has been proven to recover motor functions in rats.

Read More: Spinal Cord News and Spinal Cord 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.