How Small Molecules Control Neuron Development in the Brain: microRNAs and Autism
- Lidi Garcia
- Apr 8
- 3 min read
Researchers have discovered how tiny molecules called microRNAs help shape important neurons in the brain. They studied Purkinje cells, which control movement and are linked to autism, and showed that microRNAs are essential for the proper growth of these cells and their connections. By controlling certain genes, these molecules allow neurons to develop in the right way, paving the way for a better understanding of neurological disorders and brain development.
Our brains are made up of billions of neurons that are connected in an incredibly complex way. But how do these nerve cells know how to grow, branch, and connect correctly?
New research from Scripps Research reveals that part of this developmental “orchestra” is governed by microRNAs, tiny molecules that control when and how certain genes are turned on or off.
The scientists wanted to understand how these molecules affect the development of Purkinje cells, a special type of neuron located in the cerebellum, the part of the brain responsible for balance and motor coordination.
These cells are large, tree-like structures and are known to be important in neurodevelopmental disorders such as autism.
MicroRNAs are small pieces of RNA that do not directly produce proteins, but act as controllers for other genes, telling the body when to stop or reduce the production of certain proteins. They function as fine-tuning regulators of a very complex system, like a volume knob, adjusting how much genes are used.
To better understand this process, scientists created genetically modified mouse models that allow microRNAs to be temporarily turned on or off during specific phases of brain development.
This allowed them to see exactly when microRNAs are needed and how they affect neuron growth.
They discovered two “critical windows” in the development of Purkinje cells:
First week of life (in mice): If microRNAs are turned off here, the Purkinje cells grow with fewer branches and the cerebellum becomes smaller.
Third week of life: If microRNAs are turned off at this time, these cells cannot form synapses, which are connections with other parts of the brain, as if they had the wires but not the plugs.
They identified two key microRNAs in the development of these cells: miR-206 and miR-133. And they found four genes that these microRNAs regulate: Shank3, Prag1, En2 and Vash1.
These genes normally act as “brakes” on the growth of the cells. When microRNAs turn them off, the “brakes” are released, allowing the cell to grow its complex branching structure, essential for its function.
Interestingly, some of these genes have already been linked to disorders such as autism, which further increases scientific interest in this regulatory pathway.
This research helps to clarify how highly specialized neurons form and how subtle defects in this process can lead to neurological disorders.
In addition, it reveals how microRNAs are fundamental to the identity and function of different types of brain cells, and not just secondary support players as previously thought. Since these molecules are also involved in brain plasticity, aging, and responses to the environment, the findings may open doors to new therapeutic approaches in the future.
READ MORE:
MicroRNA mechanisms instructing Purkinje cell specification
Norjin Zolboot, Yao Xiao, Jessica X. Du, Marwan M. Ghanem, Su Yeun Choi, Miranda J. Junn, Federico Zampa, Zeyi Huang, Ian J. MacRae, and Giordano Lippi
Neuron, April 02, 2025
Abstract:
MicroRNAs (miRNAs) are critical for brain development; however, if, when, and how miRNAs drive neuronal subtype specification remains poorly understood. To address this, we engineered technologies with vastly improved spatiotemporal resolution that allow the dissection of cell-type-specific miRNA-target networks. Fast and reversible miRNA loss of function showed that miRNAs are necessary for Purkinje cell (PC) differentiation, which previously appeared to be miRNA independent, and identified distinct critical miRNA windows for dendritogenesis and climbing fiber synaptogenesis, structural features defining PC identity. Using new mouse models that enable miRNA-target network mapping in rare cell types, we uncovered PC-specific post-transcriptional programs. Manipulation of these programs revealed that the PC-enriched miR-206 and targets Shank3, Prag1, En2, and Vash1, which are uniquely repressed in PCs, are critical regulators of PC-specific dendritogenesis and synaptogenesis, with miR-206 knockdown and target overexpression partially phenocopying miRNA loss of function. Our results suggest that gene expression regulation by miRNAs, beyond transcription, is critical for neuronal subtype specification.
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