Dlk1-Dio3Locus-Derived LncRNAs Perpetuate Postmitotic Motor Neuron Cell Fate and Subtype Identity

The mammalian imprintedDlk1-Dio3locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, includingMeg3(i.e.Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By transcriptome profiling cell types at each stage of spinal cord development, we uncovered that lncRNAs expressed from theDlk1-Dio3locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically,Meg3and otherDlk1-Dio3locus-derived lncRNAs facilitate Jarid2-Ezh2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudalHoxgenes in postmitotic MNs. Our data illustrate that these lncRNAs in theDlk1-Dio3locus play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulatingHoxgenes, providing strong evidence of how lncRNAs function during embryonic development.