In many animal tissues, stem cells continually divide to create new cells that replace old or damaged cells. However, this ability requires tight control, as uncontrolled stem cell proliferation can disrupt tissue homeostasis and contribute to tumorigenesis.
Researchers at the National Institute for Physiological Sciences have identified a previously unknown mechanism that controls stem cell proliferation in the fruit fly intestine. This study revealed that smooth septum junction (sSJ) proteins, known for their role in cell-cell adhesion, regulate signaling in intestinal progenitor cell differentiation and prevent excessive stem cell proliferation.
Unraveling the signals from adhesion to growth
Previous studies by the research group have shown that loss of the sSJ protein causes hyperproliferation of Drosophila intestinal stem cells. However, the molecular mechanism behind this phenomenon remained unclear.
To solve this mystery, the research team focused on intestinal progenitor cells, which are generated from stem cells and differentiate into mature epithelial cells.
By tracking normal differentiation, the research team found that sSJ protein accumulates in the apical region of progenitor cells. At the same time, an enzyme called aPKC, a known driver of cell proliferation, is gradually removed from the same region (top diagram). In contrast, progenitor cells lacking sSJ proteins retain aPKC in their apical region (bottom).
To determine whether this aberrant localization affects stem cell behavior, the researchers artificially maintained aPKC in the apical region of progenitor cells. This manipulation was sufficient to induce excessive intestinal stem cell proliferation, indicating that spatial regulation of aPKC is essential for maintaining normal tissue homeostasis.
Further analysis revealed that persistent apical aPKC suppresses the activity of Kibra, a key activator of the Hippo signaling pathway that normally limits cell proliferation. sSJ proteins maintain Kibra function by excluding aPKC from the apical cortex, preventing activation of growth-promoting signals.
Our studies show that differentiating progenitor cells actively control stem cell proliferation through intercellular junction proteins. This discovery reveals an unexpected signaling role for intercellular adhesion molecules that goes beyond simply connecting neighboring cells. Although our study was conducted using Drosophila, the underlying principles may contribute to a deeper understanding of tissue maintenance and cancer development in higher organisms, including humans. ”
Yasushi Izumi, Associate Professor
This finding provides new insights into how epithelial tissues coordinate cell differentiation and stem cell activity to maintain tissue integrity, and may contribute to future research on tissue regeneration and cancer biology.
sauce:
Natural Science Research Organization
Reference magazines:
izumi, Y., & furuse, M. (2026) aPKC exclusion from the apical cortex of enteroblasts maintains stem cell homeostasis in Drosophila. Journal of Cell Biology. DOI: 10.1083/jcb.202509240. https://rupress.org/jcb/article-abstract/225/9/e202509240/282797/aPKC-exclusion-from-the-apical-cortex-in?redirectedFrom=fulltext
