Srebf1 Controls Midbrain Dopaminergic Neurogenesis

• Main Authors: Enrique M. Toledo, Shanzheng Yang, Daniel Gyllborg, Kim E. van Wijk, Indranil Sinha, Manuel Varas-Godoy, Christopher L. Grigsby, Peter Lönnerberg, Saiful Islam, Knut R. Steffensen, Sten Linnarsson, Ernest Arenas
• Format: Article
• Language: English
• Published: Elsevier 2020-05-01
• Series: Cell Reports
• Subjects: chromatin immunoprecipitation; single-cell RNA sequencing; radial glia; nuclear receptor; LXR; oxysterol
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720305507

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.