title: Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells.
abstract: Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden.
authors.forename: Gioele
authors.initials: G
authors.lastname: La Manno
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gyllborg
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Codeluppi
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Kaneyasu
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Carmen
authors.initials: C
authors.lastname: Salto
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden.
authors.forename: Amit
authors.initials: A
authors.lastname: Zeisel
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden.
authors.forename: Lars E
authors.initials: LE
authors.lastname: Borm
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.
authors.forename: Simon R W
authors.initials: SRW
authors.lastname: Stott
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Toledo
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Psychiatric Stem Cell Group, Neurogenetics Unit, Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Villaescusa
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönnerberg
authors.affiliation: Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Jesper
authors.initials: J
authors.lastname: Ryge
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: ernest.arenas@ki.se.
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden. Electronic address: sten.linnarsson@ki.se.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
mesh_terms: D000818:Animals; D002460:Cell Line; D000067470:Cellular Reprogramming Techniques; D059290:Dopaminergic Neurons / Q000166:cytology*; D006801:Humans; D000069550:Machine Learning; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis; D009457:Neuroglia / Q000166:cytology; D039904:Pluripotent Stem Cells / Q000166:cytology*; D017423:Sequence Analysis, RNA / Q000379:methods; D059010:Single-Cell Analysis / Q000379:methods
keywords: dopaminergic neuron; human; mouse; single-cell RNA-seq; ventral midbrain