Spatial control of astrogenesis progression by cortical arealization genes

Abstract

Sizes of neuronal, astroglial and oligodendroglial complements forming the neonatal cerebral cortex largely depend on rates at which pallial stem cells give rise to lineage-committed progenitors and the latter ones progress to mature cell types. Here, we investigated the spatial articulation of pallial stem cells’ (SCs) commitment to astrogenesis as well as the progression of committed astroglial progenitors (APs) to differentiated astrocytes, by clonal and kinetic profiling of pallial precursors. We found that caudal-medial (CM) SCs are more prone to astrogenesis than rostro-lateral (RL) ones, while RL-committed APs are more keen to proliferate than CM ones. Next, we assessed the control of these phenomena by 2 key transcription factor genes mastering regionalization of the early cortical primordium, Emx2 and Foxg1, via lentiviral somatic transgenesis, epistasis assays, and ad hoc rescue assays. We demonstrated that preferential CM SCs progression to astrogenesis is promoted by Emx2, mainly via Couptf1, Nfia, and Sox9 upregulation, while Foxg1 antagonizes such progression to some extent, likely via repression of Zbtb20. Finally, we showed that Foxg1 and Emx2 may be implicated—asymmetrically and antithetically—in shaping distinctive proliferative/differentiative behaviors displayed by APs in hippocampus and neocortex.

Phenotypic Spectrum of NFIA Haploinsufficiency: Two Additional Cases and Review of the Literature

“…P2 shows the presence of cerebral vascular malformations that have never been reported before. All these anomalies confirm the key role of NFIA in the differentiation of multiple brain areas during embryonic development [ 12 , 13 , 14 , 15 ].…”

“…Nfia knock-out mice show hydrocephalus and agenesis of the corpus callosum, and, at reduced penetrance, exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureters [ 1 , 8 ]. NFI proteins play an important role in the development of the central nervous system (CNS), including axon guidance with outgrowth and in glial or neuronal cell differentiation and migration [ 8 , 12 , 13 , 14 , 15 ].…”

Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene,Grin1

“…Foxg1 is an ancient transcription factor mastering a number of developmental processes that take place in the rostral brain. These include early activation of pan- telencephalic (Hanashima et al, 2007), subpallial (Manuel et al, 2010), and paleo-neo- pallial (Muzio and Mallamaci, 2005) programs, promotion of neural precursors selfrenewal (Martynoga et al, 2005), balance between neuronogenesis and gliogenesis (Brancaccio et al, 2010; Falcone et al, 2019; Frisari et al, 2022; Santo et al, 2022), and laminar specification of neocortical neurons (Hanashima et al, 2004; Miyoshi and Fishell, 2012; Toma et al, 2014). Later, it promotes morphological maturation of glutamatergic (Brancaccio et al, 2010; Chiola et al, 2019; Yu et al, 2019) and gabaergic (Zhu et al, 2019) telencephalic neurons.…”