Nerve networks for walking originated in ancient fish

The neural substrates of bipedalism are present in the little skate, whose common ancestor with tetrapods existed approximately 420 million years ago

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 published online 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 walking-like locomotion.

Jeremy Dasen, an associate professor at the NYU School of Medicine (Department of Neuroscience and Physiology, New York, US) comments, “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.”

“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. Until we understand how spine-limb nerve connections are wired, we can’t expect to reverse spinal cord damage and paralysis.”

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 (CPGs). Embedded in the spinal cord, such neural networks connect to 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 as genetic switches, turning genes on or off as they control the formation of motor neuronal networks.

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 the same proteins (for example ephrins) on the axons to connect to the right limb nerves.

Dasen explains: “The fact that our arms and legs function differently and independently is largely depending on the signaling of HOX genes.” 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 Dasen, authors of the study were: Heekyung Jung and Myungin Baek (NYU School of Medicine); Kristen D’Elia and David Schoppik (NYU Neuroscience Institute); Stuart Brown (NYU Center for Health Informatics and Bioinformatics ); Adriana Heguy (Genome Technology Center); Catherine Boisvert and Peter Currie (Australian Regenerative Medicine Institute, Monash University, Victoria, Australia); and Boon-Hui Ta and Byrappa Venkatesh (Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore).


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