title: FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice.
abstract: We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Henrik
authors.initials: H
authors.lastname: Ahlenius
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Soham
authors.initials: S
authors.lastname: Chanda
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Webb
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Issa
authors.initials: I
authors.lastname: Yousif
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Jesse
authors.initials: J
authors.lastname: Karmazin
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94158; Department of Neurology, University of California, San Francisco, CA 94158; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158;
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305 tcs1@stanford.edu wernig@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305; tcs1@stanford.edu wernig@stanford.edu.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071316:Forkhead Box Protein O3 / Q000172:deficiency / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse
keywords: aging; induced neuronal cells; reprogramming