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The nerve circuits that enable people to walk first appeared more than 400 million years ago in fish whose descendants still walk the seafloor on their fins. This is the finding of a study led by researchers from NYU School of Medicine and February 8 in the journal Cell.

Past research had revealed that the fish species little skate, Leucoraja erinacea, displays alternating, left–right, two-limbed motion with its pelvic fins similar to that used by land animals. The new study shows that skate—which are related to rays and sharks—use paired muscle groups, genetic regulatory proteins, and spinal cord nerve circuits similar to those used by humans to coordinate “bipedal locomotion.”

“Our study suggests that the neural circuits that control walking were established, not as our ancestors first crawled onto land as once thought, but instead long before in primitive fish,” says lead study author , associate professor in the at �ٺ���Ƶ Health.

“Given that that skates use many of the same neural circuits that we do to walk, but with six muscles instead of the hundreds we use, the fish provide a simple model to study how the circuits that enable walking are assembled,” says Dr. Dasen, a member of the at �ٺ���Ƶ Health. “Until we understand how spine–limb nerve connections are wired, we can’t expect to reverse spinal cord damage.”

Ancient Nerve Circuits

For the current study, researchers studied skate embryos because the circuits that control walking in skates and humans are formed during gestation. The researchers found that walking in both species is enabled by “central pattern generators,” or CPGs. Embedded in the spinal cord, such neural networks connect to nerve cells, called neurons, targeting limbs to enable rhythmic muscle movements like the flapping of insect wings or the running motion of human legs. The study found that skate and humans employ similar CPGs to control flexor and extensor muscles that cooperate to bend and straighten appendages.

Along with anatomical features and nerve circuitry, experiments showed that skate and mammals both use HOX and FOXP, protein groups that act “genetic switches,” turning genes on or off as they control the formation of networks of neurons that enable motion, called motor neurons.

The researchers argue that the common ancestor of fish and land animals started using these proteins to control genes related to body pattern and motion. Since then, they say, evolution has adjusted this same set of regulatory tools as fins changed to legs and wings, and even as snakes lost their limbs, reverting to a more ancient slithering program along their head-to-toe body axis. Researchers found that skates are primitive enough to have both axial and bipedal motor programs, slithering along their tails early in life, and walking later on with their pelvic fins.

In addition, humans and skate use similar mechanisms to guide nerve cells as they wire from the spinal cord into limb muscle cells. Based on genetic maps of innervation, both species for instance use dorsal neurons in the spinal CPG to control dorsal limb muscles. They also use same proteins, such as ephrins, on the tips of spinal nerve cell extensions called axons to “find” and connect to the right limb nerves.

“The fact that our arms and legs function differently and independently is largely depending on the signaling of HOX genes,” says Dr. Dasen. He says that the HOX-controlled genetic programs that humans use to move their arms and legs differently also enable the differences between pectoral forelimb and pelvic hindlimb neural circuits in skate, further validating the model.

Along with Dr. Dasen, authors of the study at NYU School of Medicine were first authors Heekyung Jung and Myungin Baek, along with Kristen D’Elia and David Schoppik in �ٺ���Ƶ’s Neuroscience Institute, Stuart Brown in �ٺ���Ƶ’s Applied Bioinformatics Laboratories, and Adriana Heguy of �ٺ���Ƶ’s Genome Technology Center. Authors also included Catherine Boisvert and Peter Currie of the Australian Regenerative Medicine Institute at Monash University in Victoria, Australia, as well as Boon-Hui Ta and Byrappa Venkatesh of the Institute of Molecular and Cell Biology at the Agency for Science, Technology, and Research, in Biopolis, Singapore.

The work was supported by National Institute of Neurological Disorders and Stroke grants R21 NS099933 and R01 NS062822, Perlmutter Cancer Center grant P30CA016087, Australian Research Council Discovery grants DP1096002 and DP160104427, and Human Frontiers Science Program grant LT000130/2009L. The work was also funded by the Biomedical Research Council of A*STAR in Singapore and by the Howard Hughes Medical Institute.

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