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Cross section of the mouse spinal cord, showing that the FoxP1 protein (red) marks the nuclei of motor neurons that innervate limb muscles. These neurons also express a retinoid synthetic enzyme RALDH2 (green) which is controlled by FoxP1 and directs later aspects of motor neuron development. Expression of FoxP1 in these neurons is essential for the activity of Hox proteins that control motor neuron diversity. Image: Tom Jessell

“It is a complicated but satisfying genetic logic, one that appears to have evolved to ensure the generation of the diverse array of motor neuron subtypes needed for fine motor control of the limbs.” Research published in the July 25, 2008, issue of Cell
Thomas M. Jessell

July 25, 2008, Howard Hughes Medical Institute – Simple, everyday movements require the coordination of dozens of muscles, guided by the activity of hundreds of motor neurons. Now, researchers have revealed an important step in the process that guides the early development of neurons themselves, as they establish the precise connections between the spinal cord and muscles. This knowledge will help scientists search for drugs to treat diseases that destroy motor neurons, such as amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

As a vertebrate organism develops, the long, outstretched processes of motor neurons wend their way from the spinal column to wire up every muscle in the body. In mammals, many hundreds of different types of motor neurons are needed to control the variety of muscle types used to coordinate movement. The highly specialized motor neurons that innervate muscles in the arms, legs, hands, and feet are the most recent of these to evolve. As an animal develops, these neurons become increasingly specialized – first establishing themselves as motor neurons, then taking on the characteristics needed to control a limb, then preparing to target a specific muscle. Proper function depends on each of these neurons finding its way from the spinal cord to the group of muscle cells that it is equipped to control.

Now, Howard Hughes Medical Institute investigator Thomas M. Jessell, working together with Jeremy Dasen of New York University and Philip Tucker of The University of Texas at Austin, has discovered the genetic recipe for making these specialized motor neurons. The key ingredient is a gene called Foxp1, which regulates the activity of a series of crucial patterning genes of the Hox family, and thereby coordinates the identity and connectivity of motor neurons. Without FoxP1, the axons of motor neurons that extend into an animal’s limb wander aimlessly and connect to muscles at random, Jessell and Dasen have found. The paper describing these findings is published in the July 25, 2008, issue of the journal Cell.

The Hox genes are among the most highly conserved of the developmental genes and are best known for their role in controlling the overall pattern of body development. Like many developmental regulators, the proteins produced by Hox genes control the activity of a diverse assortment of target genes. In previous work, Jessell, who is at Columbia University Medical Center, and Dasen discovered that 21 of the 39 mammalian Hox genes orchestrate the program of motor neuron development and connectivity. Their new work shows that FoxP1 is an essential co-factor for the entire set of Hox proteins that generate the motor neurons that control limb movement. Intriguingly, the level of FoxP1 expressed by developing motor neurons determines the precise subtype that they will form.

“This paper makes the surprising discovery that one accessory co-factor, FoxP1, is needed for the output of each of the 21 Hox proteins that make motor neurons different,” says Jessell. “Depending on which Hox gene is turned on, FoxP1 is induced to different levels. And this difference in level programs which motor neuron subtype is generated. It is a complicated but satisfying genetic logic, one that appears to have evolved to ensure the generation of the diverse array of motor neuron subtypes needed for fine motor control of the limbs.”

To emphasize the importance of this highly-evolved class of motor neurons, Jessell points to a relatively primitive vertebrate, the eel-like jawless fish known as a lamprey. “Lampreys don’t play the violin and they don’t run – their motor programs are designed for simple swimming behaviors,” Jessell says. “The lamprey represents the most extreme example of vertebrate organisms whose lifestyle permits them to survive with a highly reduced array of motor neuron subtypes.

“At some point in evolution, vertebrates acquired the ability to generate hundreds of motor neuron subtypes, presumably to accommodate the appearance of limbs new muscle classes,” says Jessell. He and his colleagues suspect this diversity may have arisen when FoxP1 began to be expressed in the spinal cord But exactly when FoxP1 expression first appeared in the spinal cord and how its expression is linked to Hox activities remain unsolved puzzles that Jessell and Dasen are now pursuing. Together with Sten Grillner of the Karolinska Institute and Manuel Pombal of the University of Vigo in Spain, they are beginning these studies by analyzing the expression and function of the FoxP1 gene in lampreys.

Jessell, Dasen, and Tucker demonstrated the significance of FoxP1 in mice by inactivating the gene and showing that the spinal cord lacked the full repertoire of motor neurons without it. “This mutation, in effect, reverts the spinal cord to a primitive ancestral state, generating a lamprey-like spinal cord encased in a mammalian body,” Jessell says. Mice without FoxP1 die before birth because the gene is also critical for heart development, so the scientists are now analyzing genetically-modified mice in which FoxP1 is deleted selectively from motor neurons. “We anticipate that these animals will have a severe impairment in motor behavior, and studying later phases of FoxP1 function should reveal insights into the assembly of motor circuits in the spinal cord as well as the periphery” he says.

Jessell’s Columbia colleagues Hynek Wichterle and Mirza Peljto, in work supported by ProjectALS, are already using the Fox-Hox recipe in their attempts to create better ways of screening for drugs to treat Lou Gehrig’s disease and other types of motor neuron degeneration. Fine-tuning the expression of the these proteins has recently permitted Wichterle and Peltjo to convert embryonic stem cells into the highly-specialized motor neurons that innervate limb muscles.

“This is a promising screening strategy for identifying drugs that prevent or slow the degeneration of motor neurons,” says Jessell. “Hopefully, many researchers will build upon these advances in basic motor neuron biology to design better and more predictive therapeutic screens.”

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HHMI INVESTIGATOR

Thomas M. Jessell, Ph.D.

5F9ECCF7-977D-4DF1-AEB7-6CBED11EAC47.jpgFor the past two decades, Thomas Jessell has worked to understand how nerve cells in the developing spinal cord assemble into functional circuits that control sensory perception and motor actions. Ultimately, his research may provide a more thorough understanding of how the central nervous system is constructed and suggest new ways to repair diseased or damaged neurons in the human brain and spinal cord.

“There is increasingly persuasive evidence to suggest that many neurodevelopmental and psychiatric disorders—from motor neuron diseases to autism and schizophrenia—result from defects in the initial assembly of connections in the developing brain,” said Jessell. “By understanding the cellular and molecular processes that control the normal wiring pattern of these connections, we may eventually be able to design more rational and effective strategies for repairing the defects that underlie brain disorders.”

Jessell’s work has revealed the details of a molecular pathway that converts naïve progenitor cells in the early neural tube into the many different classes of motor neurons and interneurons that assemble together to form functional locomotor circuits. This molecular pathway involves critical environmental signaling molecules such as Sonic hedgehog, and a delicate interplay of nuclear transcription factors that interpret Sonic hedgehog signals to generate diverse neuronal classes. The principles that have emerged from Jessell’s studies in the spinal cord have now been found to apply to many other regions of the central nervous system, thus establishing a basic ground plan for brain development. His work has also defined many of the key steps that permit newly generated neurons to form selective connections with their target cells.

One potential strategy for brain repair involves the use of stem cells, and Jessell and his colleague Hynek Wichterle recently demonstrated that mouse embryonic stem cells can be converted into functional motor neurons in a simple procedure that recapitulates the normal molecular program of motor neuron differentiation. Remarkably, these stem cell-derived motor neurons can integrate into the spinal cord in vivo and contribute to functional motor circuits. This work may uncover additional aspects of the basic program of motor neuron development, as well as pointing the way to new cell and drug-based therapies for motor neuron disease and spinal cord injury.

“I enjoy the search for answers to intriguing problems in biology,” explained Jessell. “On those rare occasions when a definitive answer emerges, there is great pleasure in having deciphered a small fragment of a much larger and still elusive puzzle. And when frustration comes, it is usually from a sense of impatience—the desire to know answers more rapidly than they emerge.”

Dr. Jessell is also Professor of Biochemistry and Molecular Biophysics and a Member of the Center for Neurobiology and Behavior at Columbia University Medical Center in New York City.

RESEARCH ABSTRACT SUMMARY:

Thomas Jessell’s research explores the mechanisms that direct the assembly of neural circuits and how the organization of these circuits controls vertebrate behavior. He is examining these general problems through an analysis of circuits in the spinal cord that coordinate locomotor behavior.

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Shizuo Kambayashi/Associated Press
Victor A. McKusick with his Japan Prize this year.

By Lawrence K. Altman, July 24, 2008, The New York Times – Dr. Victor A. McKusick, a cardiologist who went on to become a founder of medical genetics and helped make the discipline a central part of medicine, died on Tuesday at his home in Baltimore. He was 86.

The cause was complications of cancer, said officials of the Johns Hopkins University School of Medicine, where Dr. McKusick had worked for more than 60 years, including a period as physician in chief.

Dr. McKusick was also an early proponent of completely mapping the human genome, 34 years before the feat was achieved in 2003. He influenced the training of the vast majority of medical geneticists through his textbooks, which cataloged thousands of genetic disorders.

Victor Almon McKusick was born on a dairy farm in Parkman, Me., on Oct. 21, 1921. His parents were teachers. He attended grammar school in a one-room schoolhouse, and he had the same teacher for seven of the eight years.

As a child, he had planned to become a minister. Then, at 15, he developed a spreading streptococcal infection of his arm and had to spend 10 weeks in a hospital while receiving a sulfa drug, one of the first antibiotics. That experience led him to medicine.

After attending Tufts University from 1940 to 1943, he entered the Johns Hopkins medical school without receiving his bachelor’s degree.

He had intended to return to Maine to go into general practice. But he won a prestigious fellowship, and while training as a cardiologist he became fascinated by patients with unusual inherited disorders.

In 1957, Dr. McKusick established a medical genetics clinic, the same year that Dr. Arno G. Motulsky started a similar clinic at the University of Washington. They are believed to be the first medical genetics clinics in this country. It was only four years after the discovery of the structure of the DNA molecule by James Watson and Francis Crick, and one year after scientists had established that the correct number of human chromosomes was 46, a finding that helped genetics begin to flourish.

Dr. McKusick, a spry man known for his jolly sense of humor, said in an interview that in 1957 some of his colleagues “thought I was committing professional suicide in leaving cardiology to focus on rare and unimportant genetic disorders.”

Today, there are more than 100 accredited clinical genetics units in North America, with thousands of trainees.

In studying genetic disorders, Dr. McKusick kept meticulous records of the inheritance patterns and clinical features of many syndromes.

As a cardiologist in the early 1950s, Dr. McKusick became fascinated with Marfan’s syndrome, an inherited disorder in which affected patients show an array of signs, including long arms and legs and dislocated eye lenses. They often died of a rupture of the aorta, the body’s main artery.

Dr. McKusick theorized, correctly, that all of these seemingly unrelated findings were because of the action of a single abnormal gene that disturbs the formation of connective tissue.

He also studied the medical histories of members of the Old Order Amish of Pennsylvania to identify genes responsible for their inherited disorders.

Dwarfism, which was unusually common in the Amish population, was the first one that he studied in detail. He then went on to discover previously unrecognized inherited disorders.

As an avid historian of a field he helped define, Dr. McKusick told students that if they wanted to get on top of a topic, they needed to learn its course of development.

Also in the 1950s, Dr. McKusick was intrigued by genetic maps of the fruit fly and began to think seriously about a genetic map for humans. In studying links between inheritance and disease, Dr. McKusick began mapping genes on human chromosomes. And in a lecture on a landmark study in genetics at a meeting at the Hague in 1969, he made a bold proposal: he said that the time was ripe to map all the human genes as a way of understanding the basic derangements in birth defects.

“In part, the proposal reflected the exuberant mind-set that followed the first moon landing,” Dr. McKusick wrote in an autobiographical paper.

But the audience’s reaction was flat, Dr. Joseph Goldstein said in presenting him with an Albert Lasker Award in 1997 for special achievement in medicine. Dr. McKusick was the founding president of HUGO, the Human Genome Organization, a coordinating group for international genome mapping and sequencing programs, and a member of the National Academy of Sciences. He received the Gairdner award in Canada in 1977; the National Medal of Science, the United States’ highest scientific honor, in 2001; and the Japan Prize in Medical Genetics and Genomics this year.

He is survived by his wife, Anne, a rheumatologist at Johns Hopkins; two sons, Kenneth A. of Ruxton, Md., and the Rev. Victor W. of Herkimer, N.Y.; a daughter, Carol Anne of Urbana, Ill.; and his identical twin, Vincent, a retired chief justice of the Supreme Court of Maine.

July 24, 2008, The New York Times – The head of a prominent cancer research institute has warned his faculty and staff to limit cellphone use because of a possible cancer risk, The Associated Press reports.

Dr. Ronald B. Herberman, the director of the University of Pittsburgh Cancer Institute, notes that while the evidence about a cellphone-cancer link remains unclear, people should take precautions, particularly for children.

“Really at the heart of my concern is that we shouldn’t wait for a definitive study to come out, but err on the side of being safe rather than sorry later,” Dr. Herberman told The Associated Press.

Earlier this year, three prominent brain surgeons raised similar concerns while speaking on “The Larry King Show.” Their concerns were largely based on observational studies that showed only an association between cellphone use and cancer, not a causal relationship. The most important of these studies is called Interphone, a vast research effort in 13 countries, including Canada, Israel and several in Europe.

Some of the research suggests a link between cellphone use and three types of tumors: glioma; cancer of the parotid, a salivary gland near the ear; and acoustic neuroma, a tumor that essentially occurs where the ear meets the brain. All these tumors are rare, so even if cellphone use does increase risk, the risk is still very low.

On Wednesday, Dr. Herberman sent a memo to about 3,000 faculty and staff saying that children should use cellphones only for emergencies because their brains are still developing. He advised adults to keep cellphones away from the head and use the speakerphone or a wireless headset, he said.

“Although the evidence is still controversial, I am convinced that there are sufficient data to warrant issuing an advisory to share some precautionary advice on cellphone use,” he wrote in his memo.