Apoptotic neurons induce proliferative responses of progenitor cells in the postnatal neocortex

Exp Neurol. 2015 Nov:273:126-37. doi: 10.1016/j.expneurol.2015.08.010. Epub 2015 Aug 18.


Apoptotic cell death is the leading cause of neuronal loss after neonatal brain injury. Little is known about the intrinsic capacity of the immature cerebral cortex for replacing dead cells. Here we test the hypothesis that neuronal apoptosis is able to trigger compensatory proliferation in surrounding cells. In order to establish a "pure" apoptotic cell death model and to avoid the confounding effects of broken blood-brain barrier and inflammatory reactions, we used a diphtheria toxin (DT) and diphtheria toxin receptor (DTR) system to induce ablation of layer IV neurons in the rodent somatosensory cortex during the early postnatal period. We found that DT-triggered apoptosis is a slowly progressing event lasting about for 7 days. While dying cells expressed the morphological features of apoptosis, we could not detect immunoreactivity for activated caspase-3 in these cells. Microglia activation and proliferation represented the earliest cellular responses to apoptotic cell death. In addition, we found that induced apoptosis triggered a massive proliferation of undifferentiated progenitor cell pool including Sox2 as well as NG2 cells. The default differentiation pattern of proliferating progenitors appears to be the glial phenotype; we could not find evidence for newly generated neurons in response to apoptotic neuronal death. These results suggest that mitotically active progenitor populations are intrinsically capable to contribute to the repair process of injured cortical tissue and may represent a potential target for neuronal replacement strategies.

Keywords: Apoptosis; Developing brain; Diphtheria toxin; Neural progenitors; Neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology*
  • Caspase 3 / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology*
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / growth & development
  • Diphtheria Toxin / pharmacology
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Heparin-binding EGF-like Growth Factor / genetics
  • Heparin-binding EGF-like Growth Factor / metabolism
  • Homeobox Protein SIX3
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Net / drug effects
  • Nerve Net / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / physiology*
  • Neuroglia / drug effects
  • Neuroglia / physiology
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Rats
  • Rats, Wistar
  • Time Factors


  • Diphtheria Toxin
  • Eye Proteins
  • Heparin-binding EGF-like Growth Factor
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Caspase 3