Brain Development: When Cytoskeletal Proteins Play a Role in the Cell Nucleus

During brain development, neural stem cells gradually give rise to specialized nerve cells. What matters is not only which cell types are formed, but also when they arise and how they subsequently find their place in the developing tissue—such as the cerebral cortex. Researchers have often studied these processes on two levels: in the cytoskeleton, the cell’s internal framework that enables shape and movement, and in the cell nucleus, where gene expression is regulated.

A team led by Professor Magdalena Götz, a stem cell researcher at the Biomedical Center (BMC) at LMU and director of the Institute for Stem Cell Research at Helmholtz Munich, has now shown that this distinction is too simplistic. In the cell nucleus of neural stem cells, the researchers found numerous cytoskeletal proteins. Surprisingly, these proteins are present in large numbers in the cell nucleus and appear to play a role in developmental programs. One of these proteins is MAP1B—a protein whose mutations are associated with developmental disorders of the brain.

Mutations in a protein

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The study began with a comprehensive analysis of the proteins in neural stem cells. To do this, the researchers examined the cell nuclei and cytoplasm separately—both in cells from the embryonic mouse brain and in human neural stem cells derived in the laboratory from reprogrammed somatic cells. “What was surprising wasn’t that we found individual cytoskeletal proteins in the cell nucleus, but how many there were,” says Florencia Merino, first author of the study and, at the time the research was conducted, a doctoral student in Magdalena Götz’s lab. For further investigation, the team focused on the protein MAP1B. The reason: Mutations in MAP1B have already been described in people with periventricular heterotopia—a developmental disorder in which some nerve cells in the brain are not located in the correct position.

To understand the role MAP1B plays in neural stem cells, the team examined the protein’s function separately in the cytoplasm and in the nucleus. Their findings revealed a contrast: In the cytoplasm, MAP1B promotes the differentiation of neural stem cells into neurons. In the nucleus, however, MAP1B helps maintain the neural stem cell state for a longer period. “The function of MAP1B apparently depends on the part of the cell where it is active,” says Götz. “In the cytoplasm and in the nucleus, MAP1B binds to different protein complexes—and thereby influences different developmental programs.”

The findings change our understanding of periventricular heterotopia, a condition in which some nerve cells are not located where they should be during brain development. Instead of migrating into the neural layers, they remain below them in the wrong place. Until now, the obvious explanation was that the migration of these nerve cells, in particular, was disrupted.
However, the new experiments suggest that the developmental abnormality begins earlier—namely, in the neural stem cells from which the nerve cells originate: If mutations or experimental interventions disrupt the function of MAP1B at that stage, the cells remain in their stem cell program for longer. This leads to the misallocation of some of the nerve cells they form: some of them migrate more slowly and fail to reach the correct position. “Periventricular heterotopia is therefore not merely a disruption of cell migration,” says Götz. “Our results show that early misregulation of cell identity also causes the disorder.”

Changes in the cell nucleus

To examine the link to the disease more closely, the team also studied human cell models. The researchers first generated neural stem cells and used them to create three-dimensional brain organoids—laboratory-grown models of early brain structures. These organoids carried mutations in the cytoskeletal protein MAP1B that are known to occur in people with periventricular heterotopia. In the models, mutated MAP1B accumulated to a greater extent in the cell nucleus. At the same time, the researchers found nerve cells in the organoids at locations where they should not occur during normal development. Thus, the models replicated key features of the disease. “This supports our hypothesis that the increased accumulation of MAP1B in the cell nucleus contributes to the developmental abnormality,” says Götz.

But what causes MAP1B to change in the nucleus? The researchers found a clue in the so-called BAF protein complex. It influences which regions of DNA are accessible—and thus which genes can be transcribed. MAP1B binds to this complex in the nucleus. In neural stem cells with disease-associated MAP1B mutations, the binding of a key component of BAF to the DNA was altered: The complex was detected in higher concentrations in regions located near genes involved in the neural stem cell state, cell movement, and the cytoskeleton. As a result, genes involved in such developmental programs could be transcribed at the wrong time or at different levels. “What was crucial for us was that MAP1B isn’t just present in the cell nucleus,” says Merino, who is now working as a postdoc at the BMC. “It is connected there to a molecular machinery that regulates developmental programs.”

Classifying Developmental Disorders More Precisely

“Our findings offer a broader perspective on the role of the cytoskeleton in cell development, beyond MAP1B,” says Magdalena Götz. “They suggest that cytoskeletal proteins not only influence the shape and movement of cells, but may also be involved in regulating developmental programs within the cell nucleus.” Götz’s team now plans to investigate whether other cytoskeleton-associated proteins have similar functions in the cell nucleus—and whether comparable mechanisms also play a role in other stem cells and developmental processes. In the long term, this new understanding could also help classify developmental disorders more precisely: not only based on where cells end up, but also on when and how their development goes awry.

Florencia Merino, Magdalena Götz et al.: Nuclear proteome reveals microtubule-associated protein regulating fate and disease. Cell, 2026.