Neocortical astrogenesis follows neuronogenesis and precedes oligogenesis. Among key factors dictating its temporal articulation, there are progression rates of pallial stem cells (SCs) towards astroglial lineages as well as activation rates of astrocyte differentiation programs in response to extrinsic gliogenic cues. In this study, we showed that high Foxg1 SC expression antagonizes astrocyte generation, while stimulating SC self-renewal and committing SCs to neuronogenesis. We found that mechanisms underlying this activity are mainly cell autonomous and highly pleiotropic. They include a concerted downregulation of 4 key effectors channeling neural SCs to astroglial fates, as well as defective activation of core molecular machineries implementing astroglial differentiation programs. Next, we found that SC Foxg1 levels specifically decline during the neuronogenic-to-gliogenic transition, pointing to a pivotal Foxg1 role in temporal modulation of astrogenesis. Finally, we showed that Foxg1 inhibits astrogenesis from human neocortical precursors, suggesting that this is an evolutionarily ancient trait.
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.
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