Researchers Discover Key Gene for Making Motor Neurons
By Howard Hughes Medical Institute
Jul 24, 2008 - 6:25:45 PM
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(HealthNewsDigest.
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.
"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."
Thomas M. Jessell
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-
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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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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