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Cell Rep. 2014 Aug 21;8(4):1018-25. doi: 10.1016/j.celrep.2014.07.016. Epub 2014 Aug 7.

Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons.

Author information

1
Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; MRC Toxicology Unit, Leicester LE1 9HN, UK. Electronic address: lp213@leicester.ac.uk.
2
Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden.
3
Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
4
MRC Toxicology Unit, Leicester LE1 9HN, UK.
5
Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy; IRCCS Neuromed, Pozzilli IS 86077, Italy.
6
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
7
Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
8
Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: thomas.perlmann@licr.ki.se.

Abstract

Distinct midbrain dopamine (mDA) neuron subtypes are found in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), but it is mainly SNc neurons that degenerate in Parkinson's disease. Interest in how mDA neurons develop has been stimulated by the potential use of stem cells in therapy or disease modeling. However, very little is known about how specific dopaminergic subtypes are generated. Here, we show that the expression profiles of the transcription factors Sox6, Otx2, and Nolz1 define subpopulations of mDA neurons already at the neural progenitor cell stage. After cell-cycle exit, Sox6 selectively localizes to SNc neurons, while Otx2 and Nolz1 are expressed in a subset of VTA neurons. Importantly, Sox6 ablation leads to decreased expression of SNc markers and a corresponding increase in VTA markers, while Otx2 ablation has the opposite effect. Moreover, deletion of Sox6 affects striatal innervation and dopamine levels. We also find reduced Sox6 levels in Parkinson's disease patients. These findings identify Sox6 as a determinant of SNc neuron development and should facilitate the engineering of relevant mDA neurons for cell therapy and disease modeling.

PMID:
25127144
DOI:
10.1016/j.celrep.2014.07.016
[Indexed for MEDLINE]
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