title: Temporally controlled modulation of FGF/ERK signaling directs midbrain dopaminergic neural progenitor fate in mouse and human pluripotent stem cells.
abstract: Effective induction of midbrain-specific dopamine (mDA) neurons from stem cells is fundamental for realizing their potential in biomedical applications relevant to Parkinson's disease. During early development, the Otx2-positive neural tissues are patterned anterior-posteriorly to form the forebrain and midbrain under the influence of extracellular signaling such as FGF and Wnt. In the mesencephalon, sonic hedgehog (Shh) specifies a ventral progenitor fate in the floor plate region that later gives rise to mDA neurons. In this study, we systematically investigated the temporal actions of FGF signaling in mDA neuron fate specification of mouse and human pluripotent stem cells and mouse induced pluripotent stem cells. We show that a brief blockade of FGF signaling on exit of the lineage-primed epiblast pluripotent state initiates an early induction of Lmx1a and Foxa2 in nascent neural progenitors. In addition to inducing ventral midbrain characteristics, the FGF signaling blockade during neural induction also directs a midbrain fate in the anterior-posterior axis by suppressing caudalization as well as forebrain induction, leading to the maintenance of midbrain Otx2. Following a period of endogenous FGF signaling, subsequent enhancement of FGF signaling by Fgf8, in combination with Shh, promotes mDA neurogenesis and restricts alternative fates. Thus, a stepwise control of FGF signaling during distinct stages of stem cell neural fate conversion is crucial for reliable and highly efficient production of functional, authentic midbrain-specific dopaminergic neurons. Importantly, we provide evidence that this novel, small-molecule-based strategy applies to both mouse and human pluripotent stem cells.
authors: Stem Cell Neurogenesis, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, UK.
authors: Ines
authors: I
authors: Jaeger
authors: Charles
authors: C
authors: Arber
authors: Jessica R
authors: JR
authors: Risner-Janiczek
authors: Judit
authors: J
authors: Kuechler
authors: Diana
authors: D
authors: Pritzsche
authors: I-Cheng
authors: IC
authors: Chen
authors: Thulasi
authors: T
authors: Naveenan
authors: Mark A
authors: MA
authors: Ungless
authors: Meng
authors: M
authors: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008959:Models, Neurological; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D051857:Otx Transcription Factors / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D051857:Otx Transcription Factors; D051155:Wnt1 Protein; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D004298:Dopamine