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Apoptosis-resistant cells drive compensatory proliferation via cell-autonomous and non-autonomous functions of the

Tslil Braun1, Naama Afgin1, Lena Sapozhnikov1

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Nature Communications
|December 4, 2025
PubMed

Insights

This study reveals two cell populations, Dronc-activating (DARE) and non-activating (NARE) cells, crucial for tissue regeneration after radiation. DARE cells promote regeneration independently of effector caspases, highlighting new insights into cell proliferation and apoptosis resistance.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • Caspases are primarily known for inducing apoptosis.
  • Their role in compensatory proliferation during tissue regeneration is not well understood.

Purpose of the Study:

  • To investigate the function of caspases in tissue regeneration via compensatory proliferation.
  • To identify cell populations mediating regeneration after ionizing radiation in Drosophila.

Main Methods:

  • Utilized Drosophila wing discs with a delayed reporter for Dronc (initiator caspase-9 ortholog) activity.
  • Analyzed cell-autonomous and non-cell-autonomous roles of Dronc.
  • Investigated signaling pathways including TNFR, ROS, p38 MAPK, and specific myosin proteins (Myo1D, Myo7A).

Main Results:

  • Identified two apoptosis-resistant epithelial cell populations: Dronc-activating (DARE) and non-activating (NARE) cells.
  • Dronc activity in DARE cells, independent of Dark and effector caspases, drives regeneration.
  • TNFR signaling (Wengen) promotes DARE proliferation, while TNF/Eiger and TNFR (Grindelwald) suppress it.
  • p38 MAPK is essential for both DARE and NARE proliferation.
  • Myo1D promotes DARE survival by inhibiting effector caspases, while Myo7A supports moderate caspase activity.
  • Dying cells induce DARE activation, and both populations confer apoptosis resistance to progeny.

Conclusions:

  • Balanced proliferation of DARE and NARE cells is vital for effective tissue regeneration, growth, and differentiation.
  • Findings offer insights into radiation-resistant cells relevant to cancer therapy.
  • Dronc's role extends beyond apoptosis to actively driving regeneration through specific cell populations.

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