Cell found two proteins at one time that regulate the migration of neuronal and neuroblastoma cancer cells

During brain development, neurons must travel long distances in complex environments until they reach their final destination
.
To find guidance, they had to establish some interactions
between the receptor and the surrounding molecules, which are still difficult to study.
Now, a paper published in the prestigious journal Cell has identified how two different proteins, the neuronal receptor Unc5 and the molecule Glipican 3 (GPC3), work together decisively in two different processes to guide neuronal brain formation and the reproduction
of brain-derived cancer cells (neuroblastoma).

The paper identifies the points where these two proteins connect, reveals the structure of the new Unc5-GPC3 complex, and identifies its key role
in neuronal migration and certain tumors.
It also delves into the mechanisms that regulate cell migration in a precise way, and illustrates how some of the
molecular mechanisms that regulate cell migration are highly conserved between neurons and some brain tumors.

The team leading the study was made up of Daniel del Toro, experts from the Faculty of Medicine and Health Sciences of the University of Barcelona, the Institute of Neuroscience, the August Pi i Sunyer Institute for Biomedical Research (IRIBAPS) and the Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), as well as Valerie Castellani from the University of Lyon in France and Elena Seiradake from the University of Oxford in the United Kingdom
。

UNC5-GPC3 complex: protein and a glycine envelope

During the development of the cerebral cortex, neurons use fibers from stem cells, called radial glia, as a highway
to reach their final location.
During migration, neurons must interact with these fibers, but the proteins involved and how they interact are fairly unknown
.

Understanding the molecular guidance mechanisms of brain cells during brain development is a rather complex goal
.
In this study, the collaboration and expertise of three scientific teams led to the identification of the interaction between the two proteins, Unc5 and GPC3, and a detailed understanding of how they bind
through carbohydrates carried to the surface.

"This study reveals for the first time a new complex consisting of the protein Unc5 and the compound GPC3 present in neurons, which are present in
the fibers where these cells migrate.
When they interact, the Unc5-GPC3 protein complex is formed, which promotes the migration of neurons on the fiber," said
Daniel del Toro, a member of the Department of Biomedical Sciences at the University of Buffalo.

Through structural analysis of protein complexes, it became possible
to discover molecular guidance mechanisms in brain cells.
By identifying binding sites between proteins, the team was able to generate tools to control their interactions and identify the specific functions
of this protein complex.
"A very surprising result is that the complex itself regulates cell migration, just as neurons are different from
certain brain tumors, such as neuroblastoma," the researchers said.

The focus of this research is to analyze the migration of the main neurons of the cerebral cortex, a decisive process
for the correct formation of neural circuits that regulate the most complex cognitive functions (language, cognition, abstract thinking, etc.
).
However, the team found that the Unc5-GPC3 complex is present in other regions of the brain, so other neurons can also use it to migrate
.
"For example, other neurons called interneurons also reach the cerebral cortex and express proteins
from this complex.
Therefore, it will be very interesting to test the function of this complex in other neuronal types in future studies," says
Daniel del Toro.

Molecular guidelines shared by different cells

Until now, it has been thought that cells migrate using different mechanisms in a completely separate biological environment, but the new results suggest that the guiding mechanisms during cell migration can be shared and reused
by different types of cells.
This means that the knowledge tools generated in this research can be applied in very different contexts, such as the migration of other types of cells, or to apply new strategies to control certain pathological processes, such as cancer
.

It should be borne in mind that in some tumors, such as neuroblastoma, the expression of the Unc5 protein is very high
.
"Therefore, we think that this factor can also regulate the migration and spread of this tumor cell, which is the research area
of the Lyon team.
" Given that GPC3, another protein in the complex, is highly expressed in other types of tumors, it is likely that the same complex will form in other cancers
.
Therefore, the tools developed in this study will allow us to study it in future studies", points out the
expert.

The UB team focused on studying the role of
the Unc5-GPC3 complex in neuronal migration.
In the lab, the team discovered this new protein complex during brain development
.
Based on this finding, they focused their research on this complex during neuronal migration in the cerebral cortex
.
Using different techniques, they modified the binding sites of these proteins in the mouse brains, which allowed them to demonstrate their function
in the process.

Methodologically, it is also decisive to determine the binding sites between proteins by X-ray crystallography to obtain the structure of protein
complexes.
Thanks to the contribution of the Oxford team, it has been possible to develop very small antibodies (nanobodies) that can facilitate or block the formation
of such complexes.
"We have been able to introduce these nanoantibodies into the brain, while it is still in development, to see how this complex regulates the migration
of neurons.
" In addition, we apply microfluidic methods using structure-based protein engineering to study the behavior
of cortical neurons.
Del Toro said
.

A new tool to regulate the migration of neurons and tumor cells

Changes in the neuronal migration process in the cerebral cortex can lead to cognitive changes and learning problems
.
From a more clinical point of view, in tumors such as neuroblastoma, all the processes that regulate their spread have a great influence
on the prognosis of the pathology.

"The results and tools produced by the study of the Unc5-GPC3 complex in migrating neurons are ideal
for future studies of their function in the brain.
" In particular, this study gives us the tools to study the function of this complex in other systems in which it operates, such as in different areas of the brain during development or during
the migration of other tumors.
Given that the proteins that make up the complex can interact with other components, it would be interesting to
explore whether this complex could modulate the reaction of cells migrating in different environments by adding new proteins.
Researcher del Toro concluded
.

GPC3-Unc5D complex structure and role in cell migration