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1. Claustrum and dorsal endopiriform cortex complex cell-identity is determined by Nurr1 and regulates hallucinogenic-like states in mice

Author

Mantas, Ioannis, Flais, Ivana, Masarapu, Yuvarani, Ionescu, Tudor, Frapard, Solène, Jung, Felix, Le Merre, Pierre, Saarinen, Marcus, Tiklova, Katarina, Salmani, Behzad Yaghmaeian, Gillberg, Linda, Zhang, Xiaoqun, Chergui, Karima, Carlén, Marie, Giacomello, Stefania, Hengerer, Bastian, Perlmann, Thomas, and Svenningsson, Per

Published
2024
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4. Schwann cell precursors represent a neural crest‐like state with biased multipotency

Author

Kastriti, Maria Eleni, Faure, Louis, Von Ahsen, Dorothea, Bouderlique, Thibault Gerald, Boström, Johan, Solovieva, Tatiana, Jackson, Cameron, Bronner, Marianne, Meijer, Dies, Hadjab, Saida, Lallemend, Francois, Erickson, Alek, Kaucka, Marketa, Dyachuk, Viacheslav, Perlmann, Thomas, Lahti, Laura, Krivanek, Jan, Brunet, Jean‐Francois, Fried, Kaj, and Adameyko, Igor

Published
2022
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9. Parkin is not required to sustain OXPHOS function in adult mammalian tissues

Author

Filograna, Roberta, primary, Gerlach, Jule, additional, Choi, Hae-Na, additional, Rigoni, Giovanni, additional, Barbaro, Michela, additional, Oscarson, Mikael, additional, Lee, Seungmin, additional, Tiklova, Katarina, additional, Ringner, Markus, additional, Koolmeister, Camilla, additional, Wibom, Rolf, additional, Riggare, Sara, additional, Nennesmo, Inger, additional, Perlmann, Thomas, additional, Wredenberg, Anna, additional, Wedell, Anna, additional, Motori, Elisa, additional, Svenningsson, Per, additional, and Larsson, Nils-Goran, additional

Published
2023
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22. PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

Author

Toskas, Konstantinos, primary, Yaghmaeian-Salmani, Behzad, additional, Skiteva, Olga, additional, Paslawski, Wojciech, additional, Gillberg, Linda, additional, Skara, Vasiliki, additional, Antoniou, Irene, additional, Södersten, Erik, additional, Svenningsson, Per, additional, Chergui, Karima, additional, Ringnér, Markus, additional, Perlmann, Thomas, additional, and Holmberg, Johan, additional

Published
2022
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25. Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

Author

Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, Di Porzio, Umberto, Perlmann, Thomas, Caiazzo, Massimiliano, Volpicelli, Floriana, Bellenchi, Gian Carlo, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, di Porzio, Umberto, Perlmann, Thoma, Caiazzo, Massimiliano, Volpicelli, Floriana, and Bellenchi, Gian Carlo

Subjects
Nuclear Receptor Subfamily 4, Member 2, Transcription Factor, LIM-Homeodomain Proteins, LIM-Homeodomain Protein, Lmx1a, Catalysis, Inorganic Chemistry, Mice, Mesencephalon, Nuclear Receptor Subfamily 4, Group A, Member 2, Animals, Nurr1, dopamine, microRNA, Cell Differentiation, Dopamine, Transcription Factors, Dopaminergic Neurons, MicroRNAs, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Group A, Animal, Organic Chemistry, General Medicine, Computer Science Applications, Dopaminergic Neuron
Abstract

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression.

Published
2022
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26. Selective requirement for polycomb repressor complex 2 in the generation of specific hypothalamic neuronal subtypes

Author

Yaghmaeian Salmani, Behzad, Balderson, Brad, Bauer, Susanne, Ekman, Helen, Starkenberg, Annika, Perlmann, Thomas, Piper, Michael, Boden, Mikael, Thor, Stefan, Yaghmaeian Salmani, Behzad, Balderson, Brad, Bauer, Susanne, Ekman, Helen, Starkenberg, Annika, Perlmann, Thomas, Piper, Michael, Boden, Mikael, and Thor, Stefan

Abstract

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the polycomb repressor complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3, a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g. Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that most neuronal subtypes were still generated in Eed mutants. However, we observed an increase in glutamatergic/GABAergic double-positive cells, as well as loss/ reduction of dopamine, hypocretin and Tac2-Pax6 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, but points to a unique sensitivity of particular neuronal subtypes to a disrupted epigenomic landscape., Funding Agencies|VetenskapsradetSwedish Research Council [2020-00884, 621-2013-5258]; Knut och Alice Wallenbergs StiftelseKnut & Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; CancerfondenSwedish Cancer Society [140780, 150663]; University of QueenslandUniversity of Queensland; Australian Government RTP ScholarshipAustralian Government; Australian Research CouncilAustralian Research Council [DP180100017]; Torsten Soderbergs Stiftelse

Published
2022
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27. PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

Author

Toskas, Konstantinos, Yaghmaeian-Salmani, Behzad, Skiteva, Olga, Paslawski, Wojciech, Gillberg, Linda, Skara, Vasiliki, Antoniou, Irene, Södersten, Erik, Svenningsson, Per, Chergui, Karima, Ringnér, Markus, Perlmann, Thomas, Holmberg, Johan, Toskas, Konstantinos, Yaghmaeian-Salmani, Behzad, Skiteva, Olga, Paslawski, Wojciech, Gillberg, Linda, Skara, Vasiliki, Antoniou, Irene, Södersten, Erik, Svenningsson, Per, Chergui, Karima, Ringnér, Markus, Perlmann, Thomas, and Holmberg, Johan

Abstract

How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component, Eed, in these neurons resulted in global loss of H3K27me3, followed by a gradual activation of genes harboring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was lost at these PRC2 targets before gene activation. Neuronal survival was not compromised; instead, there was a reduction in subtype-specific gene expression and a progressive impairment of dopaminergic and serotonergic neuronal function, leading to behavioral deficits characteristic of Parkinson's disease and anxiety. Single-cell analysis revealed subtype-specific vulnerability to loss of PRC2 repression in dopamine neurons of the substantia nigra. Our study reveals that a PRC2-dependent nonpermissive chromatin state is essential to maintain the subtype identity and function of dopaminergic and serotonergic neurons.

Published
2022
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28. Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

Author

Afd Pharmaceutics, Pharmaceutics, Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, Di Porzio, Umberto, Perlmann, Thomas, Caiazzo, Massimiliano, Volpicelli, Floriana, Bellenchi, Gian Carlo, Afd Pharmaceutics, Pharmaceutics, Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, Di Porzio, Umberto, Perlmann, Thomas, Caiazzo, Massimiliano, Volpicelli, Floriana, and Bellenchi, Gian Carlo

Published
2022

34. Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Author

Filograna, Roberta, primary, Lee, Seungmin, additional, Tiklová, Katarína, additional, Mennuni, Mara, additional, Jonsson, Viktor, additional, Ringnér, Markus, additional, Gillberg, Linda, additional, Sopova, Elena, additional, Shupliakov, Oleg, additional, Koolmeister, Camilla, additional, Olson, Lars, additional, Perlmann, Thomas, additional, and Larsson, Nils-Göran, additional

Published
2021
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37. Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson's disease

Author

Tiklova, Katarina, Nolbrant, Sara, Fiorenzano, Alessandro, Björklund, Åsa K., Sharma, Yogita, Heuer, Andreas, Gillberg, Linda, Hoban, Deirdre B., Cardoso, Tiago, Adler, Andrew F., Birtele, Marcella, Lunden-Miguel, Hilda, Volakakis, Nikolaos, Kirkeby, Agnete, Perlmann, Thomas, Parmar, Malin, Tiklova, Katarina, Nolbrant, Sara, Fiorenzano, Alessandro, Björklund, Åsa K., Sharma, Yogita, Heuer, Andreas, Gillberg, Linda, Hoban, Deirdre B., Cardoso, Tiago, Adler, Andrew F., Birtele, Marcella, Lunden-Miguel, Hilda, Volakakis, Nikolaos, Kirkeby, Agnete, Perlmann, Thomas, and Parmar, Malin

Abstract

Cell replacement is a long-standing and realistic goal for the treatment of Parkinsons disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation, dopamine (DA) neurons are seen to be a minor component of grafts, and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single-cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of recently identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model. What happens to cells on engrafting into the brain in animal models to treat Parkinson's disease is unclear. Here, the authors use scRNA-seq to examine ventral midbrain (VM)-patterned human embryonic stem cells after functional maturation in a pre-clinical rat model for Parkinson's disease and identify perivascular-like cells.

Published
2020
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39. The establishment of neuronal properties is controlled by Sox4 and Sox11

Author

Bergsland, Maria, Werme, Martin, Malewicz, Michal, Perlmann, Thomas, and Muhr, Jonas

Subjects
Neurons -- Research, DNA binding proteins -- Structure, DNA binding proteins -- Research, Stem cell research, Biological sciences
Abstract

The role of Sox4 and Sox11 in the formation of neurons in the vertebrate CNS is examined. The results have revealed a central regulatory role of Sox4 and Sox11 during neuronal maturation and mechanistically separate cell cycle withdrawal from the establishment of neuronal properties.

Published
2006

43. [p57.sup.Kip2] cooperates with Nurr1 in developing dopamine cells

Author

Joseph, Bertrand, Wallen-Mackenzie, Asa, Benoit, Gerard, Murata, Takashi, Joodmardi, Eliza, Okret, Sam, and Perlmann, Thomas

Subjects
Proteins -- Research, Science and technology
Abstract

Cyclin-dependent kinase inhibitors of the Cip/Kip family play critical roles in regulating cell proliferation during embryogenesis. However, these proteins also influence cell differentiation by mechanisms that have remained unknown. Here we show that p[57.sup.Kip2] is expressed in postmitotic differentiating midbrain dopamine cells. Induction of [p57.sup.Kip2] expression depends on Nurr1, an orphan nuclear receptor that is essential for dopamine neuron development. Moreover, analyses of [p57.sup.Kip2] gene-targeted mice revealed that [p57.sup.Kip2] is required for the maturation of midbrain dopamine neuronal cells. Additional experiments in a dopaminergic cell line demonstrated that [p57.sup.Kip2] can promote maturation by a mechanism that does not require [p57.sup.Kip2]-mediated inhibition of cyclin-dependent kinases. Instead, evidence indicates that [p57.sup.Kip2] functions by a direct protein-protein interaction with Nurr1. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby [p57.sup.Kip2] influences postmitotic differentiation of dopamine neurons.

Published
2003

44. Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells

Author

Wallen-Mackenzie, Asa; Urquiza, Alexander Mata de;Petresson,Susanna, Rodriguez, Francisco J.; Friling, Stina; Wagner, Joseph, Ordentlich, Peter; Lengqvist, Johan, and Heyman, Richard A.;Arenas, Ernest ; Perlmann,Thomas

Subjects
Central nervous system -- Diseases, Retinoids -- Research, Biological sciences
Abstract

The presence of endogenous retinoid X receptor (RXR) ligands in the embryonic central nervous system (CNS) is demonstrated and shown that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Evidence for a role of Nurr1as a ligand-independent partner of RXR in its function as a bona fide ligand-activated nuclear receptor (NR) is provided.

Published
2003

45. Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease

Author

Tiklová, Katarína, primary, Nolbrant, Sara, additional, Fiorenzano, Alessandro, additional, Björklund, Åsa K., additional, Sharma, Yogita, additional, Heuer, Andreas, additional, Gillberg, Linda, additional, Hoban, Deirdre B., additional, Cardoso, Tiago, additional, Adler, Andrew F., additional, Birtele, Marcella, additional, Lundén-Miguel, Hilda, additional, Volakakis, Nikolaos, additional, Kirkeby, Agnete, additional, Perlmann, Thomas, additional, and Parmar, Malin, additional

Published
2020
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47. Selective requirement for polycomb repressor complex 2 in the generation of specific hypothalamic neuronal subtypes.

Author

Salmani, Behzad Yaghmaeian, Balderson, Brad, Bauer, Susanne, Ekman, Helen, Starkenberg, Annika, Perlmann, Thomas, Piper, Michael, Bodén, Mikael, and Thor, Stefan

Subjects
HYPOTHALAMUS, HOMEOBOX genes, REGULATOR genes, CELL cycle, CELL analysis, GENE flow
Abstract

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the polycomb repressor complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3, a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g. Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that most neuronal subtypes were still generated in Eed mutants. However, we observed an increase in glutamatergic/GABAergic double-positive cells, as well as loss/ reduction of dopamine, hypocretin and Tac2-Pax6 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, but points to a unique sensitivity of particular neuronal subtypes to a disrupted epigenomic landscape. [ABSTRACT FROM AUTHOR]

Published
2022
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49. Retinoid-X receptor signalling in the developing spinal cord

Author

Solomin, Ludmila, Johansson, Clas B., Zetterstrom, Rolf H., Bissonnette, Reid P., Heyman, Richard A., Olson, Lars, Lendahl, Urban, Frisen, Jonas, and Perlmann, Thomas

Subjects
Retinoids -- Research, Gene expression -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Gene expression is regulated by retinoids via the action of retinoic acid receptors (RARs) and retinoid-X receptors (RXRs). An assay in transgenic mic based on the expression of a fusion protein linking either RXR or RAR to the yeast Ga14 DNA-binding domain is described. Receptor activation in the spinal cord is detected in a pattern suggesting that the receptor operates in the maturation of limb-innervating motor neurons.

Published
1998

50. BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites

Author

Blumberg, Bruce, Heonjoong Kang, Bolado, Jack, Jr., Hongwu Chen, Craig, A. Grey, Moreno, Tanya A., Kazuhiko Umesono, Perlmann, Thomas, Robertis, Eddy M. De, and Evans, Ronald M.

Subjects
Vertebrates -- Research, DNA -- Analysis, Cell receptors -- Research, Biological sciences
Abstract

BXR, a vertebrate orphan receptor, heterodimerizes with RXR and binds DNA sites with a variant thyroid hormone response element. BXR responds to low-molecular weight molecules with distinctive spectral patterns. The bioactivity-guided screen of embryonic extracts look different from other nuclear receptor ligands. Studies such as this can lead to a new understanding of physiologic homeostasis.

Published
1998

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