Abstract
IGF1, an anabolic and neuroprotective factor, promotes neuronal survival by blocking apoptosis. It is released into the bloodstream by the liver, or synthesized locally by muscles and neural cells, acting in an autocrine or paracrine fashion. Intriguingly, genetic studies conducted in invertebrate and murine models also suggest that an excess of IGF1 signaling may trigger neurodegeneration. This emphasizes the importance of gaining a better understanding of the mechanisms controlling IGF1 regulation and gene transcription. In the cerebellum, Igf1 expression is activated just before birth in a subset of Purkinje cells (PCs). Mice carrying a null mutation for HLH transcription factor EBF2 feature PC apoptosis at birth. We show that Igf1 is sharply downregulated in Ebf2 null PCs starting before the onset of PC death. In vitro, EBF2 binds a conserved distal Igf1 promoter region. The pro-survival PI3K signaling pathway is strongly inhibited in mutant cerebella. Finally, Ebf2 null organotypic cultures respond to IGF1 treatment by inhibiting PC apoptosis. Consistently, wild type slices treated with an IGF1 competitor feature a sharp increase in PC death. Our findings reveal that IGF1 is required for PC survival in the neonatal cerebellum, and identify a new mechanism regulating its local production in the CNS.
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Abbreviations
- AKT/PKB:
-
protein kinase B
- EBF2:
-
early B-cell factor 2
- IGF1:
-
insulin-like growth factor I
- PCs:
-
Purkinje cells
- PI3K:
-
phosphatidylinositol 3-kinase
- TF:
-
trancription factor
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Acknowledgements
Image analysis was carried out at Alembic, a microscopy laboratory established by the San Raffaele Scientific Institute and Vita-Salute San Raffele University. The authors are grateful to Carla Panzeri and Alessio Palini, San Raffaele Scientific Institute, for their help with electron microscopy and cytofluorimetric analysis, respectively. We are sincerely grateful to Matthias Kieslinger (Munich) for the gift of mouse Ebf-specific shRNA vectors and Ebf2 expression vectors. GGC was supported by an Ataxia-UK grant. Additional support to this work came from Fondazione Mariani (Milan), the Italian Ministry of Health and the Canadian Institutes of Health Research.
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Croci, L., Barili, V., Chia, D. et al. Local insulin-like growth factor I expression is essential for Purkinje neuron survival at birth. Cell Death Differ 18, 48–59 (2011). https://doi.org/10.1038/cdd.2010.78
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DOI: https://doi.org/10.1038/cdd.2010.78
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