FGF2 and insulin signaling converge to regulate cyclin D expression in multipotent neural stem cells
School of Medicine
Dan Hoeppner, MD (Johns Hopkins Medical School, Lieber Institute for Brain Development)
Animals; Cell Proliferation; Cyclin D; DNA; Female; Fibroblast Growth Factor 2; Insulin; Intracellular Space; Mice; Mice, Inbred C57BL; Models, Biological; Multipotent Stem Cells; Neural Stem Cells; Protein Biosynthesis; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Signal Transduction; Transcription, Genetic
Cell Biology | Developmental Biology | Developmental Neuroscience | Molecular and Cellular Neuroscience
The ex vivo expansion of stem cells is making major contribution to biomedical research. The multipotent nature of neural precursors acutely isolated from the developing central nervous system has been established in a series of studies. Understanding the mechanisms regulating cell expansion in tissue culture would support their expanded use either in cell therapies or to define disease mechanisms. Basic fibroblast growth factor (FGF2) and insulin, ligands for tyrosine kinase receptors, are sufficient to sustain neural stem cells (NSCs) in culture. Interestingly, real-time imaging shows that these cells become multipotent every time they are passaged. Here, we analyze the role of FGF2 and insulin in the brief period when multipotent cells are present. FGF2 signaling results in the phosphorylation of Erk1/2, and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels. Insulin signals through the PI3k/Akt pathway to regulate cyclins at the post-transcriptional level. This precise Boolean regulation extends our understanding of the proliferation of multipotent NSCs and provides a basis for further analysis of proliferation control in the cell states defined by real-time mapping of the cell lineages that form the central nervous system.
DOI of Published Version
Stem Cells. 2014 Mar;32(3):770-8. doi: 10.1002/stem.1575. Link to article on publisher's site
Stem cells (Dayton, Ohio)
Adepoju, Adedamola; Micali, Nicola; Ogawa, Kazuya; Hoeppner, Daniel J.; and McKay, Ronald D.G., "FGF2 and insulin signaling converge to regulate cyclin D expression in multipotent neural stem cells" (2014). University of Massachusetts Medical School. Senior Scholars Program. Paper 202.