Foxg1 bimodally tunes L1-mRNA and -DNA dynamics in the developing murine neocortex

Foxg1 masters telencephalic development via a pleiotropic control of its articulation. L1 is a large retrotransposon family expressed within CNS and suggested to contribute to its genomic plasticity. Foxg1 represses gene transcription, and L1 elements share putative Foxg1 binding motifs, suggesting the former might limit telencephalic expression (and activity) of the latter. We tested such prediction, in vivo as well as in engineered primary neural cultures, by loss- and gain-of-function approaches. We showed that Foxg1-dependent, transcriptional L1 repression specifically occurs in neopallial neuronogenic progenitors and post-mitotic neurons, where it is supported by specific changes in the L1 epigenetic landscape. Unexpectedly, we also found that Foxg1 physically interacts with L1-mRNA and positively impacts on neonatal neopallium L1-DNA content, antagonizing the retrotranscription-suppressing activity exerted by Mov10 and Ddx39a helicases. To our knowledge, Foxg1 is the first CNS patterning gene acting as a bimodal retrotransposon modulator, limiting and promoting L1 transcription and amplification, respectively, within a specific domain of the developing mouse brain.