Foxg1 Coordinates the Switch from Nonradially to Radially Migrating Glutamatergic Subtypes in the Neocortex through Spatiotemporal Repression

Abstract

SUMMARY The specification of neuronal subtypes in the cerebral cortex proceeds in a temporal manner; however, the regulation of the transitions between the sequentially generated subtypes is poorly understood. Here, we report that the forkhead-box transcription factor Foxg1 coordinates the production of neocortical projection neurons through the global repression of a default gene program. The delayed activation of Foxg1 was necessary and sufficient to induce deep-layer neurogenesis, followed by a sequential wave of upper-layer neurogenesis. A genome-wide analysis revealed that Foxg1 binds to mammalian-specific non-coding sequences to repress over 12 transcription factors expressed in early progenitors, including Ebf2/3, Dmrt3, Dmrta1 and Eya2. These findings reveal an unexpected prolonged competence of progenitors to initiate corticogenesis at a progressed stage during development and identify Foxg1 as a critical initiator of neocorticogenesis through spatiotemporal repression, a system that balances the production of non-radially and radially migrating glutamatergic subtypes during mammalian cortical expansion.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex

“…At E12.5, Foxg1, which is required to repress Tbr1 during the transition to upper-layer neurogenesis (17), was expressed in the VZ and in early-born PP neurons (Fig. 8 A-D), as previously reported (16). A reduction in Foxg1 expression was evident in Neurog2 −/− ;Ascl1 −/− cortices, both by immunostaining (Fig.…”

“…Intrinsic signals that specify temporal identities within cortical progenitors include Foxg1, a winged-helix transcription factor that initially represses a layer I identity and later promotes deeplayer cortical fates (16). The subsequent switch from deep-to upper-layer cell fates also involves the repression of Tbr1 by Foxg1 (17).…”

“…Finally, to assess whether Neurog2 and Ascl1 confer early cortical fates via known temporal determinants, we profiled the expression of Foxg1 (16,17), Ikaros (18), and PRC1 (Rnf2) and PRC2 (Ezh2) components (19) in Neurog2;Ascl1 mutants. At E12.5, Foxg1, which is required to repress Tbr1 during the transition to upper-layer neurogenesis (17), was expressed in the VZ and in early-born PP neurons (Fig.…”

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

“…In vertebrates, Foxg1 is essential for the development of telencephalon, cell migration, and cerebral cortex patterning and layering (3,4). During early phases of cortical development, Foxg1 controls the rate of neurogenesis by keeping progenitor cells in a proliferative state and by inhibiting their differentiation into neurons (5).…”

MicroRNAs

“…Its role in HPRT deficiency was recently uncovered (Guibinga et al, 2014) through its association and partnership with the transcription factor Mash1, which was one of the first transcription factors whose expression was found to be significantly dysregulated in HPRT-deficient cells (Guibinga et al, 2010). FoxG1 has multiple functions in the developing brain, among them driving neuronal specification in the forebrain via the repression of other transcription factors in early progenitor cells (Kumamoto et al, 2013). Mutations of FoxG1 has been linked to variants of Rett syndrome that is characterized by mental retardation and movement disorder reminiscing of some of neurological phenotype associated with LND patients (Florian, Bahi-Buisson, & Bienvenu, 2012).…”