title: Directed differentiation of human embryonic stem cells into corticofugal neurons uncovers heterogeneous Fezf2-expressing subpopulations.
abstract: Understanding how neuronal diversity is achieved within the cerebral cortex remains a major challenge in neuroscience. The advent of human embryonic stem cells (hESCs) as a model system provides a unique opportunity to study human corticogenesis in vitro and to identify the mechanisms that promote neuronal differentiation to achieve neuronal diversity in human brain. The transcription factor Fezf2 is necessary and sufficient for the specification of subcerebral projection neurons in mouse. However, its function during human corticogenesis is poorly understood. This study reports the differentiation of a hFezf2-YFP hESC reporter line into corticofugal projection neurons capable of extending axons toward the spinal cord upon transplantation into neonatal mouse brains. Additionally, we show that triple inhibition of the TGFß/BMP/Wnt-Shh pathway promotes the generation of hFezf2-expressing cells in vitro. Finally, this study unveils the isolation of two novel and distinct populations of hFezf2-YFP expressing cells reminiscent of the distinct Fezf2-expressing neuronal subtypes in the developing mouse brain. Overall our data suggest that the directed differentiation of hESCs into corticofugal neurons provides a useful model to identify the molecular mechanisms regulating human corticofugal differentiation and survival.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Muriel
authors.initials: M
authors.lastname: Kmet
authors.forename: Chao
authors.initials: C
authors.lastname: Guo
authors.forename: Carina
authors.initials: C
authors.lastname: Edmondson
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology*; D033581:Stem Cell Transplantation; D014157:Transcription Factors / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; C557090:FEZF2 protein, human; D008164:Luminescent Proteins; D014157:Transcription Factors; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins