In the space of a few weeks, during embryonic development, billions of neurons in the peripheral nervous system stretch throughout the body to reach the brain, muscles and sensory system, with a precision of more than a thousandth of a millimeter. How this happens is one of the great mysteries of neuroscience.

In a study recently published in the prestigious journal Neuron, a group of researchers from San Raffaele - coordinated by Dario Bonanomi, head of the Laboratory of Molecular Neurobiology and winner of the 2015 Harvard Career Development Award - identified one of the fundamental mechanisms that allows motor neurons (the cells responsible for movement) to successfully develop to the extremities of the body, without getting in conflict with vascular cells. The undisturbed navigation of motor nerves is made possible by a gene that the researchers decided to name “Drake”, after the famous explorer and pirate Sir Francis Drake, who lived in the late 16th century.

The relationship between blood vessels and motor neurons during development

Blood vessels are typically considered “friends” of neurons, as they attract each other and form coherent networks.

“This attractive relationship, however, raises the paradox that, during the embryonic development of these structures, vessels and nerves come dangerously close together with the risk that they may interfere with each other in the formation of neural circuits, on the one hand, and vascular networks on the other. The collision between motor neurons and vessels would prevent nerves from reaching the muscle target,” says Dario Bonanomi.

How is it possible? What are the biological and chemical mechanisms behind the development of  neuro-vascular structures?

The study of San Raffaele

The study, based on experimental models, showed that our nerves are able to successfully elude obstacles to the development of neural circuits, thus continuing their journey through the nervous system undisturbed.

“In our lab we show that nerves solve the problem by balancing vessel-attracting signals (VEGF) with repulsive signals (Sema3C), both of which are released by the growing nerve fibers. That is, nerves draw vascular endothelial cells close but at the same time push them out of their path. In this way, nerves and vessels reduce the risk of collisions and reconcile the need to align to each other and assemble the neurovascular unit that is essential for nervous system metabolism” explains Bonanomi. An extremely clever mechanism, capable of reorganizing itself with a high degree of flexibility.

Already more than a century ago, in fact, the father of neurobiology Ramon y Cajal had hypothesized that nerve projections (the axons) were equipped with “battering ram” mechanical properties, necessary to avoid obstacles during the formation of neuronal circuits. However, researchers at San Raffaele demonstrated that this function is even more sophisticated and selective than expected and that the removal of cellular obstacles occurs through the release of a dedicated signal, which acts with surgical precision on specific cells among the myriad that populates the tissue in which nerves grow.

An activity that reminds us of the voyages of the most adventurous explorers of the past: the scientists have in fact renamed the gene that regulates this mechanism 'Drake', after the English explorer that completed the first circumnavigation of the globe.

When the 'Drake' gene is mutated

When mutated, the Drake gene –better known as Plexin-D1 receptor– leads the axons of motor neurons of the spinal cord to collide with what appears to be an ectopic 'vascular barrier' that forms along their route toward muscle targets.

“Although in this study we focus on embryonic development, we can imagine that a problem that adult neurons face, for instance following trauma or stroke, is that they may have lost the ability to deal with cellular obstacles, including those built by vessels that undergo substantial remodeling in pathological conditions. Studying these fundamental biological mechanisms and understanding how to reactivate them in disease settings could lead to future therapeutic benefits,” Bonanomi concludes.