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Related Concept Videos

The Ras Gene02:38

The Ras Gene

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
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Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
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MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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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
Summary
This summary is machine-generated.

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.

Keywords:
Nf1bRafCortical interneuronMAPKRASopathySomatostatin

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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.