Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Shanzheng Yang
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Daniel Gyllborg
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Kim E. van Wijk
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Indranil Sinha
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
Manuel Varas-Godoy
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Christopher L. Grigsby
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden; Division of Biomaterials, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Peter Lönnerberg
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Saiful Islam
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Knut R. Steffensen
Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
Sten Linnarsson
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden
Ernest Arenas
Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, Solnavägen 9, 17177 Stockholm, Sweden; Corresponding author
Summary: Liver X receptors (LXRs) and their ligands are potent regulators of midbrain dopaminergic (mDA) neurogenesis and differentiation. However, the molecular mechanisms by which LXRs control these functions remain to be elucidated. Here, we perform a combined transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analysis of midbrain cells after LXR activation, followed by bioinformatic analysis to elucidate the transcriptional networks controlling mDA neurogenesis. Our results identify the basic helix-loop-helix transcription factor sterol regulatory element binding protein 1 (SREBP1) as part of a cluster of proneural transcription factors in radial glia and as a regulator of transcription factors controlling mDA neurogenesis, such as Foxa2. Moreover, loss- and gain-of-function experiments in vitro and in vivo demonstrate that Srebf1 is both required and sufficient for mDA neurogenesis. Our data, thus, identify Srebf1 as a central player in mDA neurogenesis.
