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Related Concept Videos

The Ras Gene02:38

The Ras Gene

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.
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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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A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
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Costello syndrome H-Ras alleles regulate cortical development.

Annie Paquin1, Christian Hordo, David R Kaplan

  • 1Stem Cell Biology Program, Hospital for Sick Children, Toronto, Canada.

Developmental Biology
|April 18, 2009
PubMed
Summary

Genetic mutations in H-Ras cause Costello syndrome, leading to brain abnormalities. This study shows these mutations disrupt neural stem cell development, impacting neuron and glial cell formation, likely causing cognitive deficits.

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Area of Science:

  • Developmental Neuroscience
  • Molecular Genetics
  • Cell Biology

Background:

  • Costello syndrome (CS) is a genetic disorder caused by H-Ras mutations, linked to cortical abnormalities and intellectual disability.
  • The underlying cellular mechanisms contributing to cognitive deficits in CS remain unclear.

Purpose of the Study:

  • To investigate how specific H-Ras mutations found in CS affect cortical precursor cell proliferation, differentiation, and survival.
  • To determine if these cellular changes can explain the cognitive dysfunction observed in Costello syndrome.

Main Methods:

  • Expression of disease-associated H-Ras mutants (H-RasG12V, H-RasG12S) in cortical progenitor cells, both in vitro and in vivo using in utero electroporation.
  • Analysis of cell fate, including proliferation, neurogenesis, and gliogenesis.

Main Results:

  • Expression of CS H-Ras mutants inhibited neurogenesis while promoting proliferation and astrogenesis in cultured precursors.
  • In vivo, H-Ras mutants enhanced cell proliferation and suppressed neurogenesis.
  • Aberrant H-Ras activation led to premature gliogenesis, increasing astrocyte numbers postnatally.

Conclusions:

  • Aberrant H-Ras activation in cortical precursors disrupts normal neural development.
  • These perturbations in cell proliferation and differentiation contribute to cortical abnormalities and cognitive deficits in Costello syndrome.