This rabbit walks on his ‘hands’. Scientists believe they have found the genetic reason why | Science

By Elizabeth Pennisi

In 1935, French veterinarians observed a rabbit with a peculiar gait. Sometimes when walking or running, the Sauteur d’Alfort the rabbit raised its hind legs above its head, clambering across the ground with its front legs like a circus performer (see video, above).

Now, scientists have determined the genetic mutation that likely causes this breed to have this strange form of locomotion. The gene involved contains clues to how the spinal cord allows walking, jumping and even standing with the hands, a finding that fits in with other work done over the past decade in mice and horses. Together, the studies provide an emerging picture that can help explain how all vertebrates, including humans, move.

The work could help scientists treat human motor deficits like Charcot-Marie-Tooth disease, a disease of the nervous system characterized by muscle weakness, says Stephanie Koch, a neuroscientist at University College London who was not involved in any of the studies. but you have seen something similar. steps in mice. The results of the study are “surprising and exciting.”

The march is complex. The left, right, front and rear extremities must move at the right time. The muscles must contract just enough to properly bend, straighten, lift, and twist the legs. And the body has to be able to switch from, say, walking to running, or moving sideways, in an instant if the senses detect danger or obstacles.

Most of these decisions are made by a bundle of nerve cells in the spinal cord called the central pattern generator, not the brain. But it’s not clear how, says Sónia Paixão, a neuroscientist at the Max Planck Institute for Neurobiology.

Researchers know that nerve cells called interneurons, which transmit sensory information from the rest of the body to motor neurons that control muscles, play a key role. Various teams have been working to define classes of interneurons, often categorized by the genes that are active in them. Then comes the hard work of figuring out what those neurons are doing. “The exact nature and function of the relevant interneurons have been difficult to pin down,” says Abdel El Manira, a neuroscientist at the Karolinska Institute (KI).

That’s where the saute, or the jumping rabbit enters. Geneticists Leif Andersson from the University of Uppsala (USA) and Miguel Carneiro from the University of Porto decided to try to trace the DNA behind the animal’s strange gait after sequencing a rabbit genome in 2014. Jumping rabbits were mated with another breed to create first and second generation animals with normal walking or standing. The researchers then compared the DNA of affected and unaffected rabbits and determined a mutation in a gene called RORBO. Working with developmental biologist UU Klas Kullander, they tracked where and when this gene was active.

In these rabbits, the mutation causes aberrant, or sometimes none, versions of the RORB protein to occur in a specific group of interneurons, the team reports today in PLOS Genetics. This protein is a transcription factor, which means that it controls the activity of many other genes. Development studies showed that the result of two defects RORBO genes is that these interneurons are completely missing, and in rabbits with one copy there are 25% fewer of them. These interneurons are inhibitory, preventing nerve cells from firing, and when they are missing, rabbits over-flex certain muscles and raise their hind legs more than they should.

“I was impressed that the authors could identify a single genetic mutation,” says Jeremy Dasen, a neuroscientist at New York University. Because locomotion is such a complicated behavior, I expected multiple genes and multiple classes of interneurons to be involved. But this document leads home that, like modular homes with separate sections put together to make a dwelling, locomotion is achieved through the combined efforts of individual classes of interneurons, he adds.

RORBO also appears to control hind limb coordination in mice: rodents lack a function RORBO gene walk like ducks. As a result, says KI neuroscientist Sten Grillner, “the importance of RORBO it is most likely to apply to all animals with limbs ”, including humans. People with Charcot-Marie-Tooth disease also have atypical RORB proteins.

RORBO It is the second gene that Andersson’s team has identified as important to the march. In 2012, he and his colleagues linked a mutation in a protein called DMRT3, which helps researchers identify a subset of interneurons, to an unusual gait called toe. In Icelandic horses that display toes, the hind legs carry more weight than the front legs, making the gait more fluid. Andersson’s team confirmed the role of the protein by producing the same mutation in mice. Breeders have selected this mutation of the horse because the altered gait gives a very smooth ride. Some of the horses that carry this mutation can also trot and walk at high speed, making them excellent for sled racing. And there is a connection between this group of interneurons and the RORBO defect, the researchers now report: rabbits with the mutation produce many more DMRT3 interneurons. Researchers don’t yet know why.

Understanding how all the components of the nervous system interact is challenging, says Paixao. Advances such as the rabbit article illustrate the progress made possible by combining developmental, genetic, and behavioral studies. “Now we are at a crucial time to achieve these goals,” he adds. “It’s an exciting time to see all the pieces of the engine control come together.”

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