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Published on: May 12, 2015
A pooled CRISPR-based neuronal activity screen links TMEM50A-dependent MVB function to synaptic integrity and remote
Jianhui Wang1, Meiqi Liu2, Yiming Chen1
1SUSTech Homeostatic Medicine Institute, Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
We developed a new genomics platform to study brain activity. This method identified TMEM50A, a protein crucial for neuronal function, synaptic integrity, and behavior.
Area of Science:
- Neuroscience
- Genomics
- Molecular Biology
Background:
- Omics profiling advances gene discovery for brain activity.
- Functional annotation of these genes, however, lags significantly.
- Understanding gene function in neurons is critical for brain health and disease research.
Purpose of the Study:
- To establish a high-throughput functional genomics platform for interrogating neuronal activity regulators.
- To identify novel genes controlling neuronal function using this platform.
- To elucidate the role of newly identified genes in synaptic integrity and behavior.
Main Methods:
- Coupling the CaMPARI2 sensor with CRISPR interference (CRISPRi) screening in human induced pluripotent stem cell-derived neurons.
- Converting cumulative neuronal activity into a flow cytometry-readable signal for pooled screening.
- Utilizing a focused library of memory-associated genes for systematic interrogation.
Main Results:
- Successfully recovered known regulators of neuronal activity.
- Identified TMEM50A, a previously uncharacterized protein, as a key regulator.
- TMEM50A loss impaired multivesicular body (MVB) function, altered the neuronal surface proteome, reduced synapse density, and affected mouse behavior.
Conclusions:
- The developed platform enables systematic discovery of neuronal activity regulators.
- TMEM50A plays a critical role in maintaining synaptic integrity through MVB function.
- TMEM50A is essential for normal behavior, highlighting its importance in neuronal health.
