Cargando…
Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs
RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles 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 th...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281549/ https://www.ncbi.nlm.nih.gov/pubmed/37254876 http://dx.doi.org/10.1242/dev.201371 |
_version_ | 1785061023439388672 |
---|---|
author | Knowles, Sara J. Stafford, April M. Zaman, Tariq Angara, Kartik Williams, Michael R. Newbern, Jason M. Vogt, Daniel |
author_facet | Knowles, Sara J. Stafford, April M. Zaman, Tariq Angara, Kartik Williams, Michael R. Newbern, Jason M. Vogt, Daniel |
author_sort | Knowles, Sara J. |
collection | PubMed |
description | RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles 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 positive. The increase in somatostatin-positive interneurons could also be prevented by pharmacological inhibition of the core RAS/MAPK signaling pathway. 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 and related disorders. |
format | Online Article Text |
id | pubmed-10281549 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-102815492023-06-21 Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs Knowles, Sara J. Stafford, April M. Zaman, Tariq Angara, Kartik Williams, Michael R. Newbern, Jason M. Vogt, Daniel Development Research Article RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles 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 positive. The increase in somatostatin-positive interneurons could also be prevented by pharmacological inhibition of the core RAS/MAPK signaling pathway. 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 and related disorders. The Company of Biologists Ltd 2023-05-31 /pmc/articles/PMC10281549/ /pubmed/37254876 http://dx.doi.org/10.1242/dev.201371 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Knowles, Sara J. Stafford, April M. Zaman, Tariq Angara, Kartik Williams, Michael R. Newbern, Jason M. Vogt, Daniel Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title | Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title_full | Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title_fullStr | Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title_full_unstemmed | Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title_short | Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs |
title_sort | distinct hyperactive ras/mapk alleles converge on common gabaergic interneuron core programs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281549/ https://www.ncbi.nlm.nih.gov/pubmed/37254876 http://dx.doi.org/10.1242/dev.201371 |
work_keys_str_mv | AT knowlessaraj distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT staffordaprilm distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT zamantariq distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT angarakartik distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT williamsmichaelr distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT newbernjasonm distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms AT vogtdaniel distincthyperactiverasmapkallelesconvergeoncommongabaergicinterneuroncoreprograms |