Foxg1bimodally tunesL1-mRNA and -DNA dynamics in the developing murine neocortex

Abstract

Foxg1masters telencephalic development via a pleiotropic control of its articulation.L1is a large retrotransposon family expressed within CNS and suggested to contribute to its genomic plasticity. Foxg1 represses gene transcription, andL1elements 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 thatFoxg1-dependent, transcriptionalL1repression specifically occurs in neopallial neuronogenic progenitors and post-mitotic neurons, where it is supported by specific changes in theL1epigenetic landscape. Unexpectedly, we also found that Foxg1 physically interacts withL1-mRNA and positively impacts on neonatal neopalliumL1-DNA content, antagonizing the retrotranscription-suppressing activity exerted by Mov10 and Ddx39a helicases. To our knowledge,Foxg1is the first CNS patterning gene acting as a bimodal retrotransposon modulator, limiting and promotingL1transcription and amplification, respectively, within a specific domain of the developing mouse brain.