Srebf1 Controls Midbrain Dopaminergic Neurogenesis

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. [Display omitted] •Srebf1 is a direct target of LXR during ventral midbrain development•Srebf1 belongs to a proneural transcriptional network in ventral midbrain radial glia•Srebf1 regulates the expression of Foxa2 in the developing ventral midbrain in vivo•Srebf1 is required for mouse midbrain dopaminergic neurogenesis in vivo Toledo et al. 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, which regulates the expression of Foxa2 and is required for midbrain dopaminergic neurogenesis in vivo.