title: Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.
abstract: Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors--Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a--that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Massimiliano
authors: M
authors: Caiazzo
authors: Maria Teresa
authors: MT
authors: Dell'Anno
authors: Elena
authors: E
authors: Dvoretskova
authors: Dejan
authors: D
authors: Lazarevic
authors: Stefano
authors: S
authors: Taverna
authors: Damiana
authors: D
authors: Leo
authors: Tatyana D
authors: TD
authors: Sotnikova
authors: Andrea
authors: A
authors: Menegon
authors: Paola
authors: P
authors: Roncaglia
authors: Giorgia
authors: G
authors: Colciago
authors: Giovanni
authors: G
authors: Russo
authors: Piero
authors: P
authors: Carninci
authors: Gianni
authors: G
authors: Pezzoli
authors: Raul R
authors: RR
authors: Gainetdinov
authors: Stefano
authors: S
authors: Gustincich
authors: Alexander
authors: A
authors: Dityatev
authors: Vania
authors: V
authors: Broccoli
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000473:pathology; D018408:Patch-Clamp Techniques; D044968:Regenerative Medicine; D012867:Skin / Q000166:cytology; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004298:Dopamine; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C489692:Lmx1a protein, mouse