Maintenance of neural stem cell positional identity by Mixed-lineage leukemia 1

Neural stem cells (NSCs) in the developing and postnatal brain have distinct positional identities that dictate the types of neurons they generate. While morphogens initially establish NSC positional identity in the neural tube, it is unclear how such regional differences are maintained as the forebrain grows much larger and anatomically more complex. We found that the maintenance of NSC positional identity requires a Mixed-lineage leukemia 1 (Mll1)-dependent epigenetic memory system. After establishment by sonic hedgehog (SHH), ventral NSC identity became independent of this morphogen. Even transient MLL1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Thus, spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain. Differential expression of cultured V-SVZ NSCs, including Dorsal vs. Ventral NSCs, UBC-CreER;SmoF/F vs control, UBC-CreER;Mll1F/F vs control, MM-401-treated vs control, and MM-401-washed out vs control, in duplicate. Genome-wide chromatin analysis by CnR for H3K27ac, H3K4me1, HeK4me3, and H3K27me3 marks on MM-401-treated, control-treated, MM-401-washout, and control-washout ventral NSCs, in duplicate