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. 2012 Apr;16(4):789-811.
doi: 10.1111/j.1582-4934.2011.01361.x.

Transcriptional insights on the regenerative mechanics of axotomized neurons in vitro

Jian Ming Jeremy Ng  1 , Minghui Jessica Chen, Jacqueline Y K Leung, Zhao Feng Peng, Jayapal Manikandan, Robert Z Qi, Meng Inn Chuah, Adrian K West, James C Vickers, Jia Lu, Nam Sang Cheung, Roger S Chung
Affiliations

Transcriptional insights on the regenerative mechanics of axotomized neurons in vitro

Jian Ming Jeremy Ng et al. J Cell Mol Med. 2012 Apr.

Abstract

Axotomized neurons have the innate ability to undergo regenerative sprouting but this is often impeded by the inhibitory central nervous system environment. To gain mechanistic insights into the key molecular determinates that specifically underlie neuronal regeneration at a transcriptomic level, we have undertaken a DNA microarray study on mature cortical neuronal clusters maintained in vitro at 8, 15, 24 and 48 hrs following complete axonal severance. A total of 305 genes, each with a minimum fold change of ± 1.5 for at least one out of the four time points and which achieved statistical significance (one-way ANOVA, P < 0.05), were identified by DAVID and classified into 14 different functional clusters according to Gene Ontology. From our data, we conclude that post-injury regenerative sprouting is an intricate process that requires two distinct pathways. Firstly, it involves restructuring of the neurite cytoskeleton, determined by compound actin and microtubule dynamics, protein trafficking and concomitant modulation of both guidance cues and neurotrophic factors. Secondly, it elicits a cell survival response whereby genes are regulated to protect against oxidative stress, inflammation and cellular ion imbalance. Our data reveal that neurons have the capability to fight insults by elevating biological antioxidants, regulating secondary messengers, suppressing apoptotic genes, controlling ion-associated processes and by expressing cell cycle proteins that, in the context of neuronal injury, could potentially have functions outside their normal role in cell division. Overall, vigilant control of cell survival responses against pernicious secondary processes is vital to avoid cell death and ensure successful neurite regeneration.

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Figures

Fig 1
Fig 1
Pie chart annotating number and percentage of genes identified in each of the 14 biological processes. A total of 305 statistically significant regulated genes were identified by DAVID. Each gene was classified into one of its most relevant biological processes categorized according to Gene Ontology to avoid overestimation.
Fig 2
Fig 2
Comparison of biological processes associated with axotomized neurons across 8, 15, 24 and 48 hrs post-injury. Bar chart shows the distribution of up-regulated (A) and down-regulated (B) genes. Differentially transcribed genes involved in the number count were statistically significant. Overall, the genomic profiles for particular biological processes at 8 hrs were slightly distinct as compared to the other time points.
Fig 3
Fig 3
Summarized view on the regulation of selected genes (taken from gene profiles) that were involved in different major sub-processes associated with neurite regeneration after axonal injury in vitro as discussed.
See this image and copyright information in PMC

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