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bioRxiv · 10.1101/2022.08.04.502867

Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

Knowles, S. J.·Stafford, A. M.·Zaman, T.·Angara, K.·Williams, M. R.·Newbern, J. M.·Vogt, D.
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Abstract

RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. While the role of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin+. The increase in somatostatin+ interneurons could also be induced by elevated neural activity and we show the core RAS/MAPK signaling pathway is one mechanism by which this occurs. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes/disorders.

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Knowles, S. J., Stafford, A. M., Zaman, T., Angara, K., Williams, M. R., Newbern, J. M., Vogt, D.. 2022-08-05. Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs. https://doi.org/10.1101/2022.08.04.502867

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