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Chromatin-modifying factor Mll1 maintains neural stem cell regional identity in the postnatal mouse brain

  • Author(s): Delgado, Ryan N
  • Advisor(s): Reiter, Jeremy
  • et al.
Abstract

The adult ventricular-subventricular zone (V-SVZ) contains neural stem cells (NSCs) that produce neurons throughout life. NSCs in the V-SVZ are regionally heterogeneous such that those located ventrally generate different subtypes of neurons than those located dorsally. Whether epigenetic mechanisms underlie the maintenance of the regional identity of NSCs is not known. Transcriptional analysis of dorsal and ventral V-SVZ NSCs revealed an enrichment of homeotic transcription factors consistent with the embryonic origins of each region. Specifically, ventral V-SVZ NSCs were enriched for Nkx2.1, a transcription factor required to specify the ventral telencephalon during embryogenesis. Using Nkx2.1-CreER fate tracing, we found that Nkx2.1+ V-SVZ NSCs generated OB interneurons in adulthood. Embryonic fate-labeling revealed that early embryonic Nkx2.1+ cells are direct precursors to the NKX2.1+ NSCs of the postnatal V-SVZ. While sonic hedgehog (Shh) signaling is required to induce and maintain Nkx2.1 expression early in neural development, inhibition of Shh signaling by cyclopamine and vismodegib did not reduce Nkx2.1 expression in postnatal V-SVZ NSCs, suggesting that Nkx2.1 expression in the V-SVZ was being maintained epigenetically. Chromatin analysis of dorsal and ventral V-SVZ NSCs revealed Mixed-lineage leukemia 1 (MLL1) protein, a trithorax group member and H3K4 methytransferase, was enriched at the Nkx2.1 locus in ventral, but not dorsal V-SVZ NSCs. Conditional deletion of Mll1 in ventral V-SVZ NSC cultures resulted in loss of Nkx2.1 expression, but did not impair Shh pathway signaling, suggesting that Mll1 is required for the maintenance of Shh-independent Nkx2.1 expression. These data thus illustrate how the positional information provided by extrinsic cellular signals such as morphogens becomes epigenetically encoded into regionally distinct cell types. More generally, these results help explain how complex developmental information is properly maintained despite rapid tissue growth and/or dynamic changes in morphogen gradients.

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