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Cell. 2016 Oct 6;167(2):566-580.e19. doi: 10.1016/j.cell.2016.09.027.

Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells.

Author information

1
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Science for Life Laboratory, 17121 Solna, Sweden.
2
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
3
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.
4
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.
5
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.
6
Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.
7
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: ernest.arenas@ki.se.
8
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.

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.

KEYWORDS:

dopaminergic neuron; human; mouse; single-cell RNA-seq; ventral midbrain

PMID:
27716510
PMCID:
PMC5055122
DOI:
10.1016/j.cell.2016.09.027
[Indexed for MEDLINE]
Free PMC Article

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