Spatial control of astrogenesis progression by cortical arealization genes

Sizes of neuronal and glial complements forming the neonatal cerebral cortex largely depend on (1) rates at which pallial stem cells give rise to lineage committed progenitors and (2) proliferation/differentiation ratios peculiar to such progenitors. Generation of astrocytes from stem cells via committed progenitors has been finely investigated in its temporal progression. Conversely, we have only partial information about regional articulation of this process. In this study, by a variety of methods including in-vitro clonal assays, gene expression profiling, lentiviral somatic transgenesis and ad-hoc rescue assays, we investigated spatial articulation of murine, pallial stem cells commitment to astrogenesis, regional progression of astroglial progenitors to differentiated astrocytes, and molecular mechanisms controlling these phenomena. We found that neural stem cells (NSCs) originating from early (E11.5) caudo-medial (CM) pallium are more astrogenesis prone than rostro-lateral (RL)-ones. We investigated if Emx2 and Foxg1, two genes showing opposite graded expression along the CM-RL pallial axis, could be responsible for this regional astrogenic bias. We found that preferential CM-NSCs progression to astrogenesis is promoted by Emx2, mainly via Couptf1 up-regulation, while Foxg1 antagonizes such progression in RL-NSCs, likely via Zbtb20 down-regulation. Next, we found that astrogenic committed progenitors are prompted to self-renew by Foxg1 (Emx2 has been already documented to induce their differentiation). Consistently, with expression patterns of these factors, we found that the fraction of mature astrocytes among astroglial lineage cells is higher in neonatal hippocampus respect to age-matched neocortex. The scenario emerging from this analysis might reflect specific geometrical/developmental constraints of the cortical primordium, where proportionally smaller and smaller peri-ventricular sectors are in charge of generating hippocampus, neocortex and paleocortex, respectively. Not least, precocious astroglial maturation occurring in neonatal hippocampus might help dealing with special metabolic needs of this structure. The discovery of differential regional tuning of astrogenesis deepens our knowledge of fundamental control of dorsal telencephalic histogenesis. Moreover, it suggest that a regionally unbalanced, neonatal astroglial complement might worsen neurophatological presentations peculiar to FOXG1-syndrome patients.