title: FGF2 and insulin signaling converge to regulate cyclin D expression in multipotent neural stem cells.
abstract: 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.
authors.affiliation: National Institute for Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA; University of Massachusetts School of Medicine, Amherst, Massachusetts, USA.
authors.forename: Adedamola
authors.initials: A
authors.lastname: Adepoju
authors.forename: Nicola
authors.initials: N
authors.lastname: Micali
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ogawa
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hoeppner
authors.forename: Ronald D G
authors.initials: RD
authors.lastname: McKay
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D056741:Cyclin D; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016222:Fibroblast Growth Factor 2; D004247:DNA
keywords: Cell culture; Cyclin; Fibroblast growth factor; Insulin; Neural stem cell