Single Gene Regulates Motor Neurons in Spinal Cord
ScienceDaily (Sep. 12, 2010) — In a surprising and unexpected discovery, scientists at NYU Langone Medical Center have found that a single type of gene acts as a master organizer of motor neurons in the spinal cord. The finding, published in the September 9, 2010 issue of Neuron, could help scientists develop new treatments for diseases such as Lou Gehrig's disease or spinal cord injury.
This image shows the pattern of motor neuron innervation in the body of a mouse embryo. (Credit: Image courtesy of Heekyung Jung)
The "master organizer" is a member of the Hox family of genes, best known for controlling the overall pattern of body development. By orchestrating a cascade of gene expression in the early embryo, Hox genes allow for the creation of an animal's overall structure and body part orientation. Scientists first discovered the genes in fruit flies but they have since detected Hox activity in mammals. Humans harbor 39 such genes and 21 have been identified as coordinating motor neurons in the spinal cord.
"We knew that there were 21 Hox genes that determine how connections are made between motor neurons in the spinal cord and muscles in the limbs," says Jeremy S. Dasen, PhD, an associate professor in the Departments of Physiology and Neuroscience at NYU Langone Medical Center and a Howard Hughes Medical Institute Early Career Scientist. "But what was surprising to us in this study was that a single Hox gene acts as a global organizer of motor neurons and their connections. The next step will be to see how Hoxc9 in motor neurons affect motor behaviors such as walking and breathing."
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Global Control of Motor Neuron Topography Mediated by the Repressive Actions of a Single Hox Gene
Neuron, Volume 67, Issue 5, 781-796, 9 September 2010
Copyright © 2010 Elsevier Inc. All rights reserved.
10.1016/j.neuron.2010.08.008
Authors
Heekyung Jung,Julie Lacombe,Esteban O. Mazzoni,Karel F. Liem,Jonathan Grinstein,Shaun Mahony,Debnath Mukhopadhyay,David K. Gifford,Richard A. Young,Kathryn V. Anderson,Hynek Wichterle,Jeremy S. DasenSee Affiliations
Highlights
Hoxc9 mutation transforms thoracic spinal cord into a limb-level identity
Hoxc9 constrains motor neuron diversity to limb levels by repressing Hox genes
Genome-wide ChIP-seq analyses indicate Hoxc9 binds multiple regions within Hox loci
Hox repression by Hoxc9 is graded and functions independently of polycomb marks
Summary
In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb levels are, however, not well understood. We show that a single Hox gene, Hoxc9, has an essential role in organizing the motor system through global repressive activities. Hoxc9 is required for the generation of thoracic motor columns, and in its absence, neurons acquire the fates of limb-innervating populations. Unexpectedly, multiple Hox genes are derepressed in Hoxc9 mutants, leading to motor pool disorganization and alterations in the connections by thoracic and forelimb-level subtypes. Genome-wide analysis of Hoxc9 binding suggests that this mode of repression is mediated by direct interactions with Hox regulatory elements, independent of chromatin marks typically associated with repressed Hox genes.
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