When neurons involved in movement — called motor neurons — form, they must build connections that reach from the brain, brainstem, or spinal cord all the way to the head, arms, or the tips of the toes. How neurons navigate these systems and “decide” where and how to grow has largely been a mystery.

Now, a new collaborative study between Salk Institute scientists and colleagues at the San Raffaele Scientific Institute in Italy show how blood vessel genes play a critical role in motor neuron development by telling blood vessels to get out of the way.

The findings, published October 7, 2022 in the journal Neuron, provide a new understanding of how a “push-pull” relationship with blood vessels — in which growing neurons both attract blood vessels to them while also pushing them out of the way — guides the growth and development of motor neurons and, potentially, a wide variety of cell types throughout the body. The discovery also has implications for understanding diseases in which motor neuron connections are destroyed, such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA).

“This discovery reveals a set of molecular and cellular interactions that had not been understood before,” says co-corresponding author Samuel Pfaff, professor in the Gene Expression Laboratory and holder of the Benjamin H. Lewis Chair at Salk. “Our discovery of how these genes regulate blood vessel growth and neuron development has implications that range from understanding how other brain circuits form to even understanding how cancer cells interact with their environment.”

Motor neuron connections are formed during fetal development. This process of wiring the nervous system is exquisitely precise, with cells making trillions of connections that reach throughout the body. And yet the genetic process that directs this development is still poorly understood.

Prior research has focused on the role of specific genes directly related to motor neurons and how they grow. But for this study, scientists took a bigger-picture approach, looking at genes both within and outside of the nervous system.

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