Although all cells in the body contain the same genetic information, they are not identical. During early development, stem cells start in a state called “pluripotency,” meaning they can potentially become any specialized cell type, such as muscle cells, blood cells, or neurons.
The specific type of cell a stem cell becomes is determined by the biological signals and inputs it receives as it progresses through development. These signals guide the cell’s transition from an unspecialized state to a more specialized, mature form.
Alessandro Gardini, Ph. D., and his lab at The Wistar Institute focused on the signals and inputs that guide pluripotent stem cells to commit to becoming neural cells during “neurogenesis”—the process of forming the human nervous system, including the brain.
Their research uncovered a molecular “bridge” complex, shedding new light on the mechanisms of early neural development. This discovery adds valuable detail to our understanding of neurodevelopment, which is crucial for advancing knowledge of neurodevelopmental disorders and syndromes.
Dr. Gardini said, “By understanding how the nervous system develops at the earliest level, we are better positioned to assess the causes of and potential solutions to neurodevelopmental disorders. Our research provides valuable evidence that transcription factors do not solely drive neural cell development.”
The research team examined the Integrator subunit INST10, which was found to be more abundant in neural cells from the central and peripheral nervous systems than other subunits of the Integrator complex. This suggested that INST10 plays a crucial role in neural cell development.
In a cell model simulating early neural development, the researchers discovered that reducing INST10 levels caused significant changes in gene expression and led cells to deviate from developing into neural cells and instead transition toward mesenchymal cells. This confirmed that INST10 is essential for maintaining the identity of neurons during neurogenesis.
At the single-cell level, the researchers found that stem cell lines with reduced INST10 expression lost the activation of key “master neuronal genes.” Instead, these cells began to express genes typically associated with intestinal or smooth muscle cell development. This shift in gene expression confirmed that INST10 is crucial for maintaining the identity of neural cells, not only during their initial development but also throughout the life of the cell.
Journal Reference:
- Zhang, Y., Hill, C.M., Leach, K.A. et al. The enhancer module of Integrator controls cell identity and early neural fate commitment. Nat Cell Biol (2024). DOI: 10.1038/s41556-024-01556-y