Dentate gyrus development requires a cortical hem-derived astrocytic scaffold

Abstract

Astrocytes are necessary for neuronal functionality in the adult brain; but may also support embryonic development of its cytoarchitecture. They are generated after neurons from embryonic radial glial cells, following the gliogenic switch. Regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted one such factor, Sox9, early during mouse brain development and observed perturbed astrogenesis and a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting Sox9 deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH), and identified previously uncharacterized ALDH1L1+ astrocytic progenitors in the CH, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration towards the developing DG. Our results highlight the crucial role of SOX9 for astroglial potential and illustrate how formation of a local network, amidst cells originating from adjacent domains, underlays brain morphogenesis.

Dentate gyrus morphogenesis is regulated by β-CATENIN function in hem-derived fimbrial glia

“…and Cowan, W.M. 1979, Caramello et al, 2021). When chemokine signaling from CR cells is disrupted in either CXCR4 or CXCL12/SDF-1 mutants (Bagri et al, 2002; Lu et al, 2002), the DMS is perturbed.…”

“…S4A and B). Transcription factors SOX9, NFIA, and NFIB required for normal development of the fimbrial glial scaffold (Caramello et al, 2021; Bunt et al, 2017) are apparently unaltered in expression levels in upon loss of β-CATENIN (Fig. S4C and D).…”

“…Dentate granule cells, identified by PROX1 labeling, do not display Ai9 fluorescence since they are not derived from the hem (Fig. 1C, D; Caramello et al, 2021).…”

“…The cortical hem, a Wnt-rich structure in the embryonic medial telencephalon, produces several distinct lineages, including the telencephalic choroid plexus epithelium, Cajal-Retzius (CR) cells, and glia that comprise the fimbrial scaffold (Louvi et al, 2007, Gu et al, 2011). Each of these lineages contributes either secreted factors or cellular substrates that perform important functions in neocortical and hippocampal development (Caramello et al, 2021, Bagri et al, 2002, Lehtinen et al, 2011). The molecular processes that operate within hem progenitors to modulate the development of these lineages are not well understood.…”

“…This scaffold is critical in guiding both the CR cells and the DMS, therefore, it is important to understand how its organization and orientation are regulated. Factors that regulate the timing of formation (Caramello et al, 2021) or the extent of this scaffold (Barry et al, 2008) have been reported, however, mechanisms that control its organization have not yet been identified.…”