Like mountaineers, nerves need expert advice to find their way

LA JOLLA – (March 22, 2019) Similar to dozens of Sherpas guiding hikers in the high Himalayan mountains to a peak, the nervous system relies on an elaborate timing and localization of guide markers for neuronal axons – filiform projections – to successfully reach their destinations in the body. Researchers at the Salk Institute are now discovering how neurons navigate a delicate cellular environment by listening to instructions while filtering inappropriate instructions to avoid getting lost. The results appeared in neuron March 19, 2019.

"There are 100,000 billion connections in the nervous system with 20,000 genes, of which about 10 gene families are involved in axon guidance control, and we wanted to understand the intelligent genetic systems that nature has used to wire the gene. the most complicated biological machine in the universe, "says Professor Salk, Samuel Pfaff, author and researcher at the Howard Hughes Medical Institute. "Thus, we began to examine how motor neurons find their connections to the muscles of the body, which is essential for our brain to transmit information to our muscles to allow movement."

The brain controls hundreds of different muscles to allow precise movements. During development, the motoneurons in the spinal cord extend their axons outside the central nervous system to connect to the muscle cells of the body. Each motor neuron relies on a set of genes to ensure the correct growth of the axon up to the muscle.

"In the broadest sense, we hoped that by identifying the genes involved in abnormal motor neuron development, we could better understand the subtleties of cell signaling in other contexts such as cancer," says the first. author Dario Bonanomi, former postdoctoral fellow of the Pfaff laboratory, now group leader at the San Raffaele Scientific Institute. "This work not only shows us how the nervous system develops, but also how cells, more generally, communicate, move and create structures in the body."

To find genes important for axon guidance of motor neurons, the team performed a genetic and observed screening where motor neurons were developing their axons using green fluorescent proteins in a murine model that had been shown to be involved in the development of motor neurons. they had conceived. The team then plotted the axons to see when correct and incorrect growth decisions were made. Thanks to this axonal tracing, scientists have identified a gene mutation that has led to an error in the driving of motor axons. In this case, the axons of the motor neuron took detours and never connected properly to the muscles.

After further investigation, scientists discovered that these motoneurons were climbing on the edge of the spinal cord instead of coming out properly to reach their muscle targets. The team identified the gene responsible for this harmful mutation as p190, which previously played a role in cancer suppression, but was not involved in establishing neuronal connections during development.

The researchers set up a series of experiments to examine how p190 affects axons leaving the spinal cord. They discovered that although axons are normally attracted to a spinal cord protein called netrin, the p190 window acts as a shield, so axons ignore netrin and are led outside the spinal cord. spinal. Once the axons have left the central nervous system, this shield is removed. Without p190, axons are attracted to netrin and do not leave the spinal cord properly. So do not connect with the muscles.

Pfaff, Benjamin H. Lewis Chair, adds: "These results provide a mechanistic overview of the unimaginable complexity that cells use to communicate with each other."

The next step is to examine the p190 control mechanism and determine the factors that influence the timing of its activity, the researchers explain.

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Onanong Chivatakarn, Matthew J. Sternfeld, Shawn P. Driscoll, Aaron Aslanian, Karen Lettieri, Miriam Gullo, Joseph W. Lewbad and Tony Hunter of the Institute of Biological Studies Salk, as well as Fabiola Valenza and Aurora Badaloni of the San Scientific Institute Raffaele in Italy.

The work and researchers involved were supported by the Howard Hughes Medical Institute, the Sol Goldman Trust, the European Research Council's start-up grant 335590 and a career development award from the Giovanni Armenise Foundation. -Harvard.

About the Institute of Biological Studies Salk:

Each cure has a starting point. The Salk Institute embodies Jonas Salk's mission of daring to turn dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new insights into neuroscience, genetics, immunology, plant biology, and more. The Institute is an independent non-profit organization and an architectural monument: small by choice, intimate by nature and intrepid in the face of any challenge. Whether it is cancer or Alzheimer's disease, aging or diabetes, Salk is where the treatments begin. Learn more about: salk.edu.