The migration of neural stem cells in humans finally deciphered

In the human fetus, there exists a niche of neural stem cells, called bRG (basal radial glial cells), which develops significantly more than in other animals, allowing for the forming of the imposing neocortex specific to our species. A phenomenon, on which a whole new light was cast by a new study published in Neuron by Dr. Alexandre Baffet, Inserm Research Director and group leader, Cell Biology of Mammalian Neurogenesis (CNRS UMR144 / Sorbonne University) at Institut Curie, and his colleagues, including Dr. Ryszard Wimmer, a PhD student at the time of the study. "We knew that these cells multiply, but we had to understand how they then migrate instead of accumulating in one place," reveals Dr. Alexandre Baffet.

A first mechanism unveiled

One of these pathways of movement was already known and named MST (mitotic somal translocation) because it is observed during mitosis¹, but its mechanisms remained unexplained. However, not only has the team of scientists deciphered the process down to the molecular scale, but in addition, they have discovered a second one. 

By relying on the imaging of human fetal tissue in culture, as well as on cortical organoids², the researchers have indeed discovered that "the MST takes place under the action of actomyosin, a protein complex, which will bring the edges of the cell closer together," specifies Alexandre Baffet. "We assume that a game between adhesion forces and contractile forces then takes place to dissipate this pressure, and that this translates into a movement of the cell."

A slow migration, which has gone unnoticed up to now

In addition, scientists have observed another way for bRG cells to migrate: IST (interphasic stomal translocation). This one, much slower—48 hours compared to 30 minutes for the MST—and unknown until now, takes place during the interphase³  and contributes five times more than MST to the dissemination of bRG cells in the cortex of the fetus. 

Here again, the researchers have understood the mechanism, this time based on microtubules⁴, and have identified the different molecular drivers and actors. "It is not very often that a study answers more questions than it asks," states Alexandre Baffet. But this is the case with ours: we wanted to understand how bRG cells migrate in the brain, and we were able to describe the phenomenon from all angles."

Better understanding lissencephaly

By opening the way to new research on various pathologies, starting with lissencephaly⁵. In children who have this condition, the brain is smooth, because the neural cells do not organize normally. However, the study by Dr. Alexandre Baffet and his colleagues provides an explanation for the phenomenon: it reveals that certain genetic mutations at the origin of the disease impact molecules involved in the IST, and that the latter is very disrupted in the tissues of patients. 

In the case of glioblastoma⁶, this research could lead to new therapeutic options. "These tumors present populations of cells that very strongly resemble bRG cells," explains Alexandre Baffet. "However, by studying them, we noted that they also carry out MST and IST and according to the same mechanisms as in the fetus."

A hope against glioblastoma

A major discovery: it is these processes that make glioblastomas so infiltrating and therefore so difficult to treat surgically. Developing inhibitors of the molecular motors involved in IST and MST could make it possible to block the dissemination of tumor cells in the brain and therefore facilitate their treatment.

Building on these advances, Dr. Alexandre Baffet will continue, with his colleagues at PEPR Cell-ID⁷, to study bRG cells and to try to understand this time how and why uncontrolled amplification sometimes takes place and leads to pediatric tumors, in particular in the cerebellum. 

[1] The moment when the cell splits in two

[2] Groups of cultured cells reproducing human brain development

[3] Period, during which the cell prepares for mitosis, in particular by duplicating its chromosomes

[4] Filaments constituting the cytoskeleton of the cell

[5] Diseases leading in particular to psychomotor retardation

[6] The most common malignant brain tumor in adults

[7] Research program "Cellular Identities and Destinies"

Reference: R. Wimmer et al., Two Translocation Mechanisms Drive Neural Stem Cell Dissemination into the Human Fetal Cortex, Neuron, forthcoming