LINE-1 retrotransposon activation intrinsic to interneuron development

Retrotransposons are a reservoir of cis-regulatory innovation 1–3 . Developmental programs that activate these elements could, in principle, manifest in lineage-specific retrotransposition. Somatic LINE-1 (L1) retrotransposon insertions have been detected in human and non-human primate neurons 4–7 . It is however unknown whether L1 is mobile in only some neuronal lineages, or therein regulates neurodevelopmental genes. Here, we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development 8–10 . PV + neurons permit L1 mobilization in vitro and in vivo , harbor unmethylated L1 promoters, and express full-length L1 mRNAs and proteins. Via nanopore long-read sequencing, we identify unmethylated L1 promoters proximal to PV + neuron genes. One such L1, which promotes transcription of a novel CAPS2 gene isoform, significantly enhances neuron morphological complexity when phenotyped in vitro . These data highlight the contribution made by L1 cis-regulatory elements to PV + neuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.