title: Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons.
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.
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; MRC Toxicology Unit, Leicester LE1 9HN, UK. Electronic address: lp213@leicester.ac.uk.
authors.forename: Lia
authors.initials: L
authors.lastname: Panman
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Papathanou
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Laguna
authors.affiliation: MRC Toxicology Unit, Leicester LE1 9HN, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Oosterveen
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Volakakis
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy; IRCCS Neuromed, Pozzilli IS 86077, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Acampora
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Idha
authors.initials: I
authors.lastname: Kurtsdotter
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitake
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden.
authors.forename: Eliza
authors.initials: E
authors.lastname: Joodmardi
authors.affiliation: Ludwig Institute for Cancer Research, 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Muhr
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy; IRCCS Neuromed, Pozzilli IS 86077, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
mesh_terms: D000818:Animals; D019521:Body Patterning; D059290:Dopaminergic Neurons / Q000502:physiology*; D006801:Humans; D008822:Mice, Transgenic; D009928:Organ Specificity; D051857:Otx Transcription Factors / Q000502:physiology*; D055755:SOXD Transcription Factors / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000196:embryology / Q000378:metabolism
chemical_list: D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse