During brain development, neural stem cells gradually differentiate into specialized neurons. The timing of when these cell types emerge and how they find their place in the developing tissue, such as in the cerebral cortex, plays a critical role. Researchers have typically investigated these processes at two levels: the cytoskeleton—the cell’s internal scaffolding that provides shape and movement—and the nucleus, where genetic programs are regulated.
A team led by Prof. Magdalena Götz from the Helmholtz Munich Institute for Stem Cell Research has revealed that this separation is overly simplistic.
In the nuclei of neural stem cells, the researchers discovered numerous cytoskeletal proteins. Surprisingly, these proteins are plentiful in the nucleus and appear to participate in developmental programs. One such protein is MAP1B, mutations of which are linked to brain developmental disorders.
MAP1B as a Key Factor in Neural Stem Cell Development
The study’s foundation was a comprehensive analysis of proteins in neural stem cells. Researchers separately examined cell nuclei and cytoplasm from both embryonic mouse brain cells and human neural stem cells derived from reprogrammed body cells.
“What surprised us was not just the presence of individual cytoskeletal proteins in the nucleus, but the sheer number of them,” says Dr. Florencia Merino, the study’s first author and a doctoral candidate in Götz’s lab at the time of research.
For further investigation, the team focused on MAP1B. This focus stemmed from prior findings that mutations in MAP1B have been documented in individuals with periventricular heterotopia—a developmental disorder where some neurons do not reach their correct positions in the brain.
Contrasting Functions of MAP1B in Cytoplasm and Nucleus
To understand MAP1B’s role in neural stem cells, the team examined the protein’s functions in both the cytoplasm and the nucleus. They found a striking contrast: in the cytoplasm, MAP1B promotes the differentiation of neural stem cells into neurons. Conversely, in the nucleus, MAP1B helps maintain the neural stem cell state longer.
“The function of MAP1B evidently depends on where it is active in the cell,” states Götz. “In both the cytoplasm and nucleus, MAP1B binds to different protein complexes, influencing various developmental programs.”
Developmental Abnormalities Initiate Earlier Than Previously Thought
The findings challenge the conventional view of periventricular heterotopia, where neurons fail to migrate properly to their destined layers. It was previously assumed that the primary issue was the migration of these neurons.
However, the new experiments suggest that the developmental abnormalities commence earlier—specifically within the neural stem cells from which the neurons originate. If mutations or experimental interventions disrupt MAP1B function at this stage, the cells remain longer in their stem-cell program. Consequently, this leads to misplacement of some neurons as they migrate slower and fail to reach the correct position.
“Periventricular heterotopia is thus not solely a migration disorder,” explains Götz. “Our findings indicate that early disruptions in cell identity also contribute to the condition.”
Brain Organoids Confirm the Role of MAP1B Mutations
To explore the disease connection further, the team studied human cell models. They first created neural stem cells and subsequently developed three-dimensional brain organoids—lab-cultivated models of early brain structures. These organoids carried MAP1B mutations associated with periventricular heterotopia.
In these models, mutated MAP1B accumulated significantly in the nucleus. Simultaneously, the researchers observed neurons forming in locations where they should not appear during normal development, thereby replicating key characteristics of the disorder.
“This supports our hypothesis that the increased accumulation of MAP1B in the nucleus contributes to developmental abnormalities,” remarks Götz.
MAP1B Influences Gene Regulation via the BAF Protein Complex
So, what changes does MAP1B initiate in the nucleus? One clue lies in the BAF protein complex, which dictates which DNA regions are accessible—and thus which genes can be read.
MAP1B binds to this complex in the nucleus. In neural stem cells with disease-associated MAP1B mutations, the binding of a crucial BAF component to DNA changed: the complex was more often found near genes involved in the neural stem cell state, cell movement, and cytoskeleton. As a result, genes participating in such developmental programs may be read at incorrect times or with varying intensity.
“It was crucial for us to establish that MAP1B is not just present in the nucleus,” states Merino. “It interacts there with a molecular machinery that regulates developmental programs.”
Implications for Future Research on Brain Developmental Disorders
“Our findings, beyond MAP1B, broaden the perspective on the role of the cytoskeleton in cell development,” says Magdalena Götz. “They suggest that cytoskeletal proteins not only influence cell shape and movement but also participate in the regulatory processes of developmental programs within the nucleus.”
Götz’s team plans to investigate whether additional cytoskeleton-associated proteins have similar functions in the nucleus, and if comparable mechanisms are at play in other stem cells and developmental processes. Ultimately, this new understanding may help classify developmental disorders more precisely, not just by where cells end up but also by when and how their development is misdirected.
Source: Helmholtz Munich
Original Publication: Merino et al.; Nuclear proteome reveals microtubule-associated protein regulating fate and disease; Cell, 2026; DOI: 10.1016/j.cell.2026.05.019
