The motor neurons that Neuron grows are guided by the "love-hate relationship" of blood vessels

When motor-related neurons — called motor neurons — form, they must make connections that extend from the brain, brainstem, or spinal cord all the way to the tips
of the head, arms, or toes.
How neurons navigate these systems and "decide" where and how to grow has largely been a mystery
.

Now, scientists at the Salk Institute and colleagues at the San Rafael Institute of Science in Italy have conducted a new collaborative study that reveals how vascular genes play a key role
in the development of motor neurons by telling them to give way.

The findings, published in the October 7, 2022 issue of the journal Neuron, provide a new understanding
of the "push-pull" relationship between blood vessels.
In this relationship, growing neurons both attract blood vessels to them and push them aside, directing the growth and development of motor neurons and possibly various cell types throughout the body
.
The findings also contribute to understanding diseases in which motor neuron connections are disrupted, such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA).

"This discovery reveals a range of molecular and cellular interactions that were previously not understood," said
co-corresponding author Samuel Pfaff.
"Our findings about how these genes regulate blood vessel growth and neuronal development have far-reaching implications
, from understanding how other brain circuits are formed to understanding even how cancer cells interact with the environment.
"

Motor neuron connections are formed
during fetal development.
This process of connecting the nervous system is very precise, and cells form trillions of connections
throughout the body.
However, the genetic processes that guide this development are still poorly
understood.
Previous research has focused on the role of specific genes directly related to motor neurons and how they grow.

But in this study, the scientists took a more macroscopic approach, looking at genes
inside and outside the nervous system.

The researchers randomly selected the mice's genetic mutations and scrutinized the developing motor neurons
in these animals.
To their surprise, they found that rats with abnormal motor neuron growth had mutations that affected not the nervous system but the vascular system
, including blood vessels.
In healthy mice, motor neurons can grow from the spinal cord and travel through surrounding tissues to distant muscle groups
.
However, the scientists observed that in mice with vascular mutations, motor neurons appeared to get stuck behind
a barrier of blood vessels.
They found that this mutation affected the ability of
blood vessels to sense close to neurons and give way.

"There is a collision between growing axons and vascular cells," said
co-corresponding author Dario Bonanomi, head of the Molecular Neurobiology Group at the San Rafael Institute of Science in Milan, Italy, and a former Salk researcher.
"When you take this receptor out of the blood vessel cells, the motor axons collide with the blood vessels, and their movement towards the muscles is damaged and hindered
.
"

The discovery reveals the delicate process of developing neurons that need to attract blood vessels to fuel their growth, while also repelling blood vessels to make way for them
.
This is related to the hurdles that must be overcome to develop motor neuron "replacement therapies" using stem cells, a potential treatment for degenerative motor neuron diseases, including amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis (SMA).

In the future, the scientists plan to study the "interaction" between nerves and blood vessels in other contexts, and how the nerve and vascular system responds
to stroke, brain injury and degenerative diseases such as atrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis (SMA).

Luis F.
Martins, Ilaria Brambilla, Alessia Motta, Stefano de Pretis, Ganesh Parameshwar Bhat, Aurora Badaloni, Chiara Malpighi, Neal D.
Amin, Fumiyasu Imai, Ramiro D.
Almeida, Yutaka Yoshida, Samuel L.
Pfaff, Dario Bonanomi.
Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity.
Neuron, 2022