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Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance

Izumi Kaji1,2, Joseph T Roland1,2, Sudiksha Rathan-Kumar1,2

  • 1Section of Surgical Sciences and.

JCI Insight
|July 1, 2021
PubMed

Insights

Loss of myosin Vb (MYO5B) impairs intestinal cell differentiation, reducing tuft cells and increasing Paneth cells. This suggests potential therapeutic strategies for microvillus inclusion disease (MVID) involving Notch inhibition or LPA treatment.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Developmental Biology

Background:

  • Myosin Vb (MYO5B) is crucial for intestinal epithelial cell function, and its loss causes microvillus inclusion disease (MVID).
  • The effect of MYO5B loss on intestinal epithelial cell lineage determination was previously unexamined.

Purpose of the Study:

  • To investigate the impact of MYO5B deficiency on differentiated epithelial cell populations in the intestine.
  • To explore the roles of lysophosphatidic acid (LPA) and Wnt/Notch signaling in MYO5B-related intestinal dysfunction.

Main Methods:

  • Utilized tamoxifen-inducible, epithelial cell-specific MYO5B-knockout mice (VilCreERT2 Myo5bfl/fl).
  • Quantified differentiated epithelial cell populations using digital image analysis and RNA-sequencing.
  • Administered intraperitoneal lysophosphatidic acid (LPA) and Notch inhibitor dibenzazepine (DBZ) to assess signaling pathway effects.

Main Results:

  • MYO5B loss led to a significant reduction in tuft cells and an increase in Paneth cells, with an expanded progenitor cell zone.
  • Lysophosphatidic acid (LPA) treatment increased tuft cell populations in both control and MYO5B-deficient mice.
  • MYO5B deficiency downregulated Wnt ligands, while Notch signaling remained active; Notch inhibition restored secretory cell populations.

Conclusions:

  • MYO5B loss impairs intestinal progenitor cell differentiation, partly due to Wnt/Notch signaling imbalance.
  • Notch inhibition and/or LPA treatment show promise as potential therapeutic strategies for MVID.
Keywords:
Epithelial transport of ions and waterGastroenterologyGenetic diseasesProtein traffic

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