Abstract
In mammals, programmed cell death (PCD) is a central event during brain development. Trophic factors have been shown to prevent PCD in postmitotic neurons. Similarly, cytokines have neurotrophic effects involving regulation of neuronal survival. Nevertheless, neuronal PCD is only partially understood and host determinants are incompletely defined. The present study provides evidence that the cytokine interleukin-9 (IL-9) and its receptor specifically control PCD of neurons in the murine newborn neocortex. IL-9 antiapoptotic action appeared to be time-restricted to early postnatal stages as both ligand and receptor transcripts were mostly expressed in neocortex between postnatal days 0 and 10. This period corresponds to the physiological peak of apoptosis for postmitotic neurons in mouse neocortex. In vivo studies showed that IL-9/IL-9 receptor pathway inhibits apoptosis in the newborn neocortex. Furthermore, in vitro studies demonstrated that IL-9 and its receptor are mainly expressed in neurons. IL-9 effects were mediated by the activation of the JAK/STAT (janus kinase/signal transducer and activator of transcription) pathway, whereas nuclear factor-κB (NF-κB) or Erk pathways were not involved in mediating IL-9-induced inhibition of cell death. Finally, IL-9 reduced the expression of the mitochondrial pro-apoptotic factor Bax whereas Bcl-2 level was not significantly affected. Together, these data suggest that IL-9/IL-9 receptor signaling pathway represents a novel endogenous antiapoptotic mechanism for cortical neurons by controlling JAK/STAT and Bax levels.
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Abbreviations
- BCL3:
-
B-cell CLL/lymphoma 3
- BDNF:
-
brain-derived neurotrophic factor
- DIV:
-
days in vitro
- dl:
-
deep layer
- E:
-
embryonic day
- Fr:
-
frontal cortex
- GFAP:
-
glial fibrillary acidic protein
- HPRT:
-
hypoxanthine-guanine phosphoribosyl-transferase
- IGF-1:
-
insulin-like growth factor-1
- IκB:
-
inhibitor of κB
- IL:
-
interleukin
- IL-9R:
-
interleukin-9 receptor
- IL-9R KO:
-
IL-9 receptor knockout mice
- I.p.:
-
intraperitoneal
- IRS:
-
insulin receptor substrate
- JAK/STAT:
-
janus kinase/signal transducer and activator of transcription
- M1:
-
primary motor cotex
- mMCP-1:
-
mouse mast cell protease-1
- NF-κB:
-
nuclear factor-κB
- NT4:
-
neurotrophin-4
- P:
-
postnatal day
- PBS:
-
phosphate buffer saline
- Parth:
-
parthenolide
- PCD:
-
programmed cell death
- PI3K:
-
phosphatidyl-inositol 3-kinase
- PKB:
-
protein kinase B
- S1:
-
primary somatosensory cortex
- Sp:
-
septum
- St:
-
striatum
- Stau:
-
staurosporine
- TGF-β:
-
transforming growth factor-β
- TCR-β:
-
T-cell receptor-β
- TUNEL:
-
terminal transferase dUTP nick end-labeling
- up:
-
upper layer
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Acknowledgements
We thank Leslie Schwendimann, Danielle Rouellé and Véronique Massonneau for excellent technical assistance. This work was financially supported by Inserm and the Université Paris 7. RF was a recipient of graduate student fellowship from national foundations including APETREIMC, CDI, SESEP and FRM. VD was financially supported by a graduate student fellowship from the Fondation Motrice. VL was financially supported by a postdoctoral fellowship from FRM.
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Fontaine, R., Cases, O., Lelièvre, V. et al. IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis. Cell Death Differ 15, 1542–1552 (2008). https://doi.org/10.1038/cdd.2008.79
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DOI: https://doi.org/10.1038/cdd.2008.79
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