NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network
- 16 July 2009
- journal article
- research article
- Published by Wiley in Journal of Neuroscience Research
- Vol. 88 (1), 33-54
- https://doi.org/10.1002/jnr.22182
Abstract
During neurogenesis, expression of the basic helix‐loop‐helix NeuroD6/Nex1/MATH‐2 transcription factor parallels neuronal differentiation and is maintained in differentiated neurons in the adult brain. To dissect NeuroD6 differentiation properties further, we previously generated a NeuroD6‐overexpressing stable PC12 cell line, PC12‐ND6, which displays a neuronal phenotype characterized by spontaneous neuritogenesis, accelerated NGF‐induced differentiation, and increased regenerative capacity. Furthermore, we reported that NeuroD6 promotes long‐term neuronal survival upon serum deprivation. In this study, we identified the NeuroD6‐mediated transcriptional regulatory pathways linking neuronal differentiation to survival, by conducting a genome‐wide microarray analysis using PC12‐ND6 cells and serum deprivation as a stress paradigm. Through a series of filtering steps and a gene‐ontology analysis, we found that NeuroD6 promotes distinct but overlapping gene networks, consistent with the differentiation, regeneration, and survival properties of PC12‐ND6 cells. By using a gene‐set‐enrichment analysis, we provide the first evidence of a compelling link between NeuroD6 and a set of heat shock proteins in the absence of stress, which may be instrumental in conferring stress tolerance on PC12‐ND6 cells. Immunocytochemistry results showed that HSP27 and HSP70 interact with cytoskeletal elements, consistent with their roles in neuritogenesis and preserving cellular integrity. HSP70 also colocalizes with mitochondria located in the soma, growing neurites, and growth cones of PC12‐ND6 cells prior to and upon stress stimulus, consistent with its neuroprotective functions. Collectively, our findings support the notion that NeuroD6 links neuronal differentiation to survival via the network of molecular chaperones and endows the cells with increased stress tolerance.Keywords
This publication has 124 references indexed in Scilit:
- Chaperones in control of protein disaggregationThe EMBO Journal, 2008
- Local translation and directional steering in axonsThe EMBO Journal, 2007
- Growth cone response to ephrin gradients produced by microfluidic networksAnalytical and Bioanalytical Chemistry, 2007
- The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functionsFEBS Letters, 2007
- Function and translational regulation of mRNA in developing axonsSeminars in Cell & Developmental Biology, 2007
- Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channelsThe Journal of cell biology, 2006
- Asymmetrical β-actin mRNA translation in growth cones mediates attractive turning to netrin-1Nature Neuroscience, 2006
- The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperonesCellular and Molecular Life Sciences, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Modulation of neurodegeneration by molecular chaperonesNature Reviews Neuroscience, 2005