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November 04, 2005
Scientists Crack Code for Motor Neuron Wiring
Howard Hughes Medical Institute (HHMI) researchers have deciphered a
key part of the regulatory code that governs how motor neurons in the
spinal cord connect to specific target muscles in the limbs.
The researchers said that understanding this code may help guide
progress in restoring motor neuron function in people whose spinal
cords have been damaged by trauma or disease. The studies suggest that
the code — which involves members of the family of transcription
factors encoded by the Hox genes — could also govern the
establishment of other spinal cord circuits. This circuitry includes
interneurons that control motor neuron firing patterns and sensory
neurons that transmit feedback information on muscle action.
“While these are basic studies on circuitry in the central nervous system, I think they offer the potential of understanding circuits in sufficient detail to guide approaches to therapy, in a clinical context.”
Thomas M. Jessell
The research team, which was led by HHMI investigator Thomas M.
Jessell, published its findings in the November 4, 2005, issue of the
journal Cell. Jessell collaborated on the studies with HHMI
research associate Jeremy S. Dasen, Bonnie C. Tice and Susan
Brenner-Morton, all of whom are at Columbia University. The work was
also funded by grants from the National Institute of Neurological
Disorders and Stroke and Project ALS.
 | | | | |  | | | | | |  |  | Spinal cord showing motor pools
Transverse sections of spinal cord... more | |
| | | | | | |  | | Spinal cord stained with antibodies
Transverse sections of chick spinal cord stained with antibodies... more
Images: Jeremy Dasen, HHMI at Columbia University | |
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According to Jessell, members of the Hox gene family had been
known to regulate aspects of brain development, but “few people
had paid attention to the fact that these genes are also expressed in
the spinal cord.” Earlier work performed by Dasen and Jessell, in
collaboration with Jeh-Ping Liu, who is now at the University of
Virginia, established that certain Hox proteins control the
differentiation of motor neurons into columns in the spinal cord. These
columns, which are arrayed along the anterior-posterior length of the
spinal cord, form in the initial phases of motor neuron organization.
That organization determines whether motor neurons grow to the limbs or
to other targets.
Creation of antibodies that react with each of the 21 Hox proteins
expressed by spinal cord motor neurons was an important technical
advance that enabled the researchers to crack this code. Using these
antibodies, Dasen and colleagues pinpointed the pattern of expression
of each protein within the set of motor neurons that project to limb
muscles. “Once we had these reagents, we were able to obtain the
high resolution maps of Hox expression that were necessary to address
more complex aspects of Hox function in motor neuron
diversification,” said Jessell.
To give an idea of the extent of complexity, Jessell explained,
“there are few motor columns, yet within each of the columns that
projects to the limb there are at least fifty different subtypes of
motor neurons, termed motor pools. Our initial work hinted that the Hox
code that defines column identity might also be involved in
establishing the extreme diversity of motor pools.”
Using antibodies to the Hox proteins that define spinal motor
neurons, Dasen and colleagues mapped the timing and location of each of
the Hox proteins expressed by motor neurons that project to the wing in
chick embryos. “It became clear that these proteins weren't
randomly expressed, but were expressed in highly precise patterns that
corresponded to anatomically-defined motor neuron pools,” said
Jessell.
Dasen's functional analysis revealed a Hox coding hierarchy.
“He found that the Hox proteins involved in pool identity are
different from those involved in column identity,” said Jessell.
“So from these data, the idea began to emerge that within the
chromosomal Hox clusters, some Hox proteins are dedicated to broad
aspects of motor neuron differentiation, and others to finer aspects of
diversification. Ultimately, what crystallized from these experiments
was a code — an organized relationship between Hox proteins, their
chromosomal organization, and the differentiation and connectivity of
motor neuron pools,” he said.
Jessell said this code appears to govern three levels of motor
neuron organization: the columnar organization that ensures that motor
neurons project into the limb; the divisional organization of motor
neurons that determines whether motor neurons project to muscles in the
dorsal or ventral halves of the limb; and finally, the motor neuron
pool identity that governs the muscle target of each set of motor
neurons. In a key set of experiments, Dasen showed that alterations in
Hox expression patterns in specific neurons resulted in changes in
motor neuron identity, and in their connectivity to muscle targets.
Marc Tessier-Lavigne, an expert in the study of how the brain is
wired and a senior vice president for research at Genentech, said the
study represents “a technical tour-de-force” and provides a
key conceptual advance for the field. “The discovery of this
molecular code shows how the nervous system can generate the huge
diversity of neurons necessary for a complex task like
locomotion.” And, he says, the fact that the code is based on Hox
genes, which regulate anterior-posterior pattern, comes as a surprise.
“The discovery that Hox genes are also used to subdivide motor
pools at particular anterior-posterior levels was unexpected. It’s
a wonderful solution to the problem of specifying this very large
number of motor pools.”
The studies also raise the possibility that the combinatorial code
contains additional information, beyond the regulation of motor neuron
wiring. “This is still conjecture, but the sheer number of Hox
proteins, and their capacity to direct neuronal differentiation,
suggests that they may also impart identity to the interneurons that
enable them to connect selectively with motor neurons. And, aspects of
the code could also give identity to sensory neurons, enabling their
connections with motor neurons,” said Jessell. Deciphering the
entire Hox code could provide crucial insights into the organization of
the complex circuitry that the spinal cord uses to control muscle
action.
According to Tessier-Lavigne, not only is the cracking of the motor
neuron code profoundly enabling for fundamental neurobiology research,
but it may have significant clinical implications, as well.
“Understanding what regulates the formation of these circuits
provides essential information for attempts to restore their integrity
and function following spinal cord injury or neurodegenerative
disease,” he said.
Jessell, too, is optimistic that there will eventually be clinical
value in deciphering the Hox code. “In developing ways to recover
from spinal cord injuries, much attention has focused on getting the
axons of cortical neurons to grow past the lesion site and innervate
target neurons in distant parts of the spinal cord,” he said.
“Now, it may be that the spinal cord circuit is still intact —
and there is some evidence to believe this — so all you need to do is
get regenerating axons to grow past the site of the lesion.
“Or, it could be that injury causes subtle alterations in the
wiring of spinal circuits, and these alterations may constrain the
capacity for full recovery of motor function. So, the more that is
understood about the basic workings of this locomotor circuit, the
better chance there is of developing regenerative strategies to restore
motor function in a precise way,” Jessell continued. “And
in motor neuron degenerative diseases, it may not be enough to make new
motor neurons; they have to connect to the right muscle target in order
to restore motor function. Understanding how Hox proteins control
circuit formation in the spinal cord should provide an important basic
framework for approaching these clinical issues.
“Thus, while these are basic studies on circuitry in the
central nervous system, I think they offer the potential of
understanding circuits in sufficient detail to guide approaches to
therapy, in a clinical context,” said Jessell.
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Versión en español
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Jim Keeley
