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RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes

Joel Johansson1, Mate Naszai2, Michael C Hodder1

  • 1Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.

Cell Stem Cell
|March 12, 2019
PubMed

Insights

RAL GTPases are crucial for intestinal stem cell function and tissue regeneration in both flies and mice. These proteins promote Wnt signaling, essential for maintaining stem cell numbers and repair capabilities.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Gastroenterology

Background:

  • Ral GTPases are effector molecules of RAS, implicated in RAS-mutant cancers.
  • Their roles in stem cell biology and tissue homeostasis remain largely unexplored.

Purpose of the Study:

  • To investigate the function of Ral GTPases in intestinal stem cells (ISCs) and tissue regeneration.
  • To elucidate the molecular mechanisms by which Ral GTPases influence Wnt signaling in ISCs.

Main Methods:

  • Utilized Drosophila melanogaster as a model organism to study RalA in ISCs.
  • Generated murine models with genetic deletion of Rala and Ralb to assess their roles in the mammalian intestine.
  • Analyzed ISC function, Lgr5 expression, Wnt signaling sensitivity, and tissue regeneration capacity following damage.
  • Investigated the effect of RALA and RALB on the internalization of the Wnt receptor Frizzled-7.

Main Results:

  • RalA expression was identified in Drosophila intestinal stem cells and progenitor cells.
  • RalA is essential for efficient regeneration downstream of Wnt signaling in Drosophila ISCs.
  • Genetic deletion of Rala or Ralb in mice reduced ISC function, Lgr5 positivity, and impaired regeneration.
  • Ablation of both Rala and Ralb led to rapid crypt death in the murine intestine.
  • RALA and RALB are required for the efficient internalization of the Wnt receptor Frizzled-7.

Conclusions:

  • RAL GTPases play a conserved role in promoting optimal Wnt signaling.
  • This function is critical for defining intestinal stem cell number and regenerative potential.
  • RAL GTPases represent a potential therapeutic target for modulating stem cell behavior in tissue repair and cancer.
Keywords:
Frizzled-7Ral GTPasesWnt signalingWnt signalosomeintestinal homeostasisintestinal stem cellsreceptor internalizationregenerationstem cell dynamics

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