NGF and proNGF regulate functionally distinct mRNAs in PC12 cells: an early gene expression profiling

The biological activities of NGF and of its precursor proNGF are quite distinct, due to different receptor binding profiles, but little is known about how proNGF regulates gene expression. Whether proNGF is a purely pro-apoptotic molecule and/or simply a "less potent NGF" is still a matter...

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Bibliographic Details
Published in:PloS one 2011-06, Vol.6 (6), p.e20839-e20839
Main Authors: D'Onofrio, Mara, Paoletti, Francesca, Arisi, Ivan, Brandi, Rossella, Malerba, Francesca, Fasulo, Luisa, Cattaneo, Antonino
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimers disease
Analysis
Animals
Apoptosis
Bioinformatics
Biology
Biosynthesis
Brain research
Cholesterol
DNA microarrays
Furin
Gene expression
Gene Expression Profiling
Gene Expression Regulation
Gene families
Gene regulation
Genes
Genetic research
Genomes
Growth factors
Humans
Kinases
Messenger RNA
Microarray Analysis
Nerve growth factor
Nerve Growth Factors - genetics
Nerve Growth Factors - metabolism
Neurodegeneration
Neurons
PC12 Cells
Pheochromocytoma cells
Protein Precursors - genetics
Protein Precursors - metabolism
Proteins
Rats
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Signaling
Spinal cord injuries
Transcription
Tumor necrosis factor-TNF
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Summary:The biological activities of NGF and of its precursor proNGF are quite distinct, due to different receptor binding profiles, but little is known about how proNGF regulates gene expression. Whether proNGF is a purely pro-apoptotic molecule and/or simply a "less potent NGF" is still a matter of debate. We performed experiments to address this question, by verifying whether a proNGF specific transcriptional signature, distinct from that of NGF, could be identified. To this aim, we studied gene expression regulation by proNGF and NGF in PC12 cells incubated for 1 and 4 hours with recombinant NGF and proNGF, in its wild-type or in a furin-cleavage resistant form. mRNA expression profiles were analyzed by whole genome microarrays at early time points, in order to identify specific profiles of NGF and proNGF. Clear differences between the mRNA profiles modulated by the three neurotrophin forms were identified. NGF and proNGF modulate remarkably distinct mRNA expression patterns, with the gene expression profile regulated by NGF being significantly more complex than that by proNGF, both in terms of the total number of differentially expressed mRNAs and of the gene families involved. Moreover, while the total number of genes modulated by NGF increases dramatically with time, that by proNGFs is unchanged or reduced. We identified a subset of regulated genes that could be ascribed to a "pure proNGF" signalling, distinct from the "pure NGF" one. We also conclude that the composition of mixed NGF and proNGF samples, when the two proteins coexist, influences the profile of gene expression. Based on this comparison of the gene expression profiles regulated by NGF and its proNGF precursor, we conclude that the two proteins activate largely distinct transcriptional programs and that the ratio of NGF to proNGF in vivo can profoundly influence the pattern of regulated mRNAs.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0020839