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

Sara J Knowles1, April M Stafford2, Tariq Zaman2

  • 1School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.

Development (Cambridge, England)
|May 31, 2023
PubMed

Insights

RAS/MAPK pathway overactivation in developing brain cells alters GABAergic interneuron programs. This research reveals how mutations impact neurodevelopment, potentially informing treatments for related cognitive disorders.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • RAS/MAPK pathway dysfunction is linked to cancers and neurocognitive disorders.
  • The role of RAS/MAPK genes in neurodevelopment is less understood than in cancer.
  • Convergent effects of RAS/MAPK gene mutations on brain phenotypes could impact multiple disorders.

Purpose of the Study:

  • To investigate the cellular and molecular effects of hyperactivating the RAS/MAPK pathway in cortical GABAergic interneurons.
  • To identify common GABAergic programs altered by distinct RAS/MAPK gene mutations.
  • To explore the potential for pharmacological intervention in RAS/MAPK-mediated neurodevelopmental changes.

Main Methods:

  • Utilized two distinct genes to hyperactivate the RAS/MAPK pathway in cortical GABAergic interneurons.
  • Assessed cellular and molecular consequences of pathway hyperactivation.
  • Examined the impact of pharmacological RAS/MAPK pathway inhibition.

Main Results:

  • Identified common GABAergic core programs altered in both hyperactive RAS/MAPK mutants.
  • Demonstrated that hyperactive RAS/MAPK mutants bias developing cortical interneurons towards a somatostatin-positive fate.
  • Showed that pharmacological inhibition of RAS/MAPK signaling can prevent the increase in somatostatin-positive interneurons.

Conclusions:

  • RAS/MAPK pathway hyperactivation converges on GABAergic interneurons during neurodevelopment.
  • Distinct RAS/MAPK mutations may share common downstream effects on interneuron development.
  • Findings offer insights into neurodevelopmental disorders associated with RAS/MAPK pathway genes and suggest therapeutic targets.
Keywords:
Nf1bRafCortical interneuronMAPKRASopathySomatostatin

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