Genomic Instructions for Building a Brain

July 6, 2018
Manuel Baizabal
Manuel Baizabal

By Manuel Baizabal, PhD
Postdoctoral Fellow,
Harwell Lab

The instructions for the production and assembly of the brain are encoded in our genome. Neural stem cells execute these instructions to generate and organize billions of neurons that comprise our brain. This process depends on the activity of non-coding regulatory DNA sequences that control the expression of thousands of genes. However, until recently how the activity of the regulatory DNA landscape in neural stem cells determines the position of each neuron in the mature brain remained unknown.

We are excited to have published a new study shedding some light on this long-standing mystery. We have discovered how the genetic information inside the nucleus of neural stem cells (also known as radial glia) determines the final position of cortical neurons. Using mice as an experimental model, we describe how PRDM16—a protein that regulates gene expression in neural stem cells—is critical to guide cortical neurons to their final destination in the cerebral cortex. In the absence of PRDM16 activity in neural stem cells, their neuronal progeny lose the normal path of migration and become misplaced in the brain. This discovery indicates that cortical neurons need the right stem cell lineage or pedigree to reach to their final positions. An intriguing question remained: how is it possible that PRDM16 influences the destiny of cortical neurons that do not produce this protein?

Harwell lab image
This artwork is a metaphor for how the position of neurons in the cerebral cortex is determined by the activity of regulatory DNA in neural stem cells. The nucleus of neural stem cells is represented as an earth-like globe using DNA to depict the coordinates. The activity of specific DNA regions—highlighted in yellow—is what determines the position of neurons, which are shown figuratively in the globe. (Created by Mao Miyamoto)

We found that PRDM16 modifies the activity of thousands non-coding regulatory DNA sequences, known as enhancers. Fine-tuning of enhancer activity in neural stem cells turned out to be critical to unleash the correct activation of genes that control the number and position of cortical neurons. Strikingly, lack of PRDM16 in the cortex led to aberrant gene expression not only in neural stem cells, but also in their migrating neuronal progeny—which never expressed PRDM16. Our observation suggests the existence of transient molecular “memory” in newborn neurons as a key process to establish the complex architecture of the cerebral cortex. Knowledge of how a neuron’s lineage history determines its final position in the brain could advance our understanding of some neurodevelopmental disorders.

Read the full study here >>

Baizabal, J.-M., Mistry, M., García, M.T., Gómez, N., Olukoya, O., Tran, D., Johnson, M.B., Walsh, C.A., and Harwell, C.C. (2018). The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls Cortical Neuron Position. Neuron 98(5), 1–18. DOI: 10.1016/j.neuron.2018.04.033.

 

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