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Antagonism between JAK/STAT downstream targets controls stem cell proliferation, cell fate conversion and

Hanfei Zhao1, Min Wei1, Ruiyan Kong1

  • 1Laboratory of Stem Cell Biology, College of Life Sciences, Capital Normal University, Beijing 100048, China.

Development (Cambridge, England)
|October 6, 2025
PubMed

Insights

The JAK/STAT pathway regulates stem cell behavior in Drosophila testes. UBR5, a JAK/STAT target, controls stem cell proliferation and fate by degrading Drumstick, maintaining tissue homeostasis.

Area of Science:

  • Stem cell biology
  • Molecular mechanisms of cell fate determination
  • Drosophila melanogaster as a model organism

Background:

  • Adult stem cells are crucial for tissue homeostasis, but the regulation of their proliferation and differentiation by niche signals is not fully understood.
  • The JAK/STAT signaling pathway plays a significant role in stem cell regulation within various tissues.

Purpose of the Study:

  • To systematically identify downstream targets of the JAK/STAT pathway in adult Drosophila testes.
  • To elucidate the molecular mechanisms by which these targets regulate stem cell proliferation, differentiation, and cell fate conversion.

Main Methods:

  • Multi-omics approaches to identify JAK/STAT downstream targets.
  • Genetic manipulation (depletion and ectopic expression) of identified genes in Drosophila.
  • Analysis of stem cell proliferation, differentiation, and cell fate using microscopy and genetic assays.
  • Protein interaction and ubiquitination assays to determine molecular mechanisms.

Main Results:

  • UBR5, a HECT-type E3 ligase, was identified as a JAK/STAT target.
  • Depletion of UBR5 in somatic cyst cells disrupted cyst stem cell (CySC) and germline stem cell (GSC) proliferation and differentiation.
  • UBR5-deficient cells exhibited a cell fate conversion towards quiescent somatic cells.
  • UBR5 mediates poly-ubiquitination and proteolysis of Drumstick (Drm), another JAK/STAT target.
  • Ectopic Drm expression mimicked UBR5 depletion phenotypes, and Drm removal suppressed UBR5 depletion defects.
  • UBR5's role in stem cell regulation is evolutionarily conserved.

Conclusions:

  • Antagonism between JAK/STAT targets, specifically UBR5 and Drm, controls JAK/STAT signaling duration, thereby regulating stem cell proliferation, differentiation, and cell fate conversion in the testicular niche.
  • This study uncovers a novel mechanism for controlling stem cell behavior crucial for tissue homeostasis and potentially relevant to tumorigenesis.
Keywords:
Cyst stem cellDrmE3 ligaseHydTestisUBR5

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