Specific Glial Populations Regulate Hippocampal Morphogenesis

Abstract

The hippocampus plays an integral role in spatial navigation, learning and memory, and is a major site for adult neurogenesis. Critical to these functions is the proper organization of the hippocampus during development. Radial glia are known to regulate hippocampal formation, but their precise function in this process is yet to be defined. We find that in Nuclear Factor I b (Nfib)-deficient mice, a subpopulation of glia from the ammonic neuroepithelium of the hippocampus fail to develop. This results in severe morphological defects, including a failure of the hippocampal fissure, and subsequently the dentate gyrus, to form. As in wild-type mice, immature nestin-positive glia, which encompass all types of radial glia, populate the hippocampus in Nfib-deficient mice at embryonic day 15. However, these fail to mature into GLAST-and GFAP-positive glia, and the supragranular glial bundle is absent. In contrast, the fimbrial glial bundle forms, but alone is insufficient for proper hippocampal morphogenesis. Dentate granule neurons are present in the mutant hippocampus but their migration is aberrant, likely resulting from the lack of the complete radial glial scaffold usually provided by both glial bundles. These data demonstrate a role for Nfib in hippocampal fissure and dentate gyrus formation, and that distinct glial bundles are critical for correct hippocampal morphogenesis.

NFIA Controls Telencephalic Progenitor Cell Differentiation through Repression of the Notch Effector Hes1

“…Like Nfia, Nfib is expressed by progenitor cells within the hippocampal ventricular zone (supplemental Figs. 7,8, available at www.jneurosci.org as supplemental material), and Nfib Ϫ/Ϫ mice display delays in hippocampal astrocyte development (Barry et al, 2008). Furthermore, Hes1 mRNA levels are significantly higher in the hippocampus of Nfib Ϫ/Ϫ mice than that of controls, and chromatin immunoprecipitation experiments demonstrate that the basal Hes1 promoter is bound by NFIB in vivo (supplemental Fig.…”

“…1G). Mature hippocampal glia and dentate granule neurons, both of which originate in the ammonic ventricular zone, are essential for morphogenesis of the dentate gyrus (Zhou et al, 2004;Barry et al, 2008). Thus, the severe reduction of this structure in the Nfia Ϫ/Ϫ mice is likely to be the culmination of the delayed differentiation of ventricular zone-derived progenitors.…”

“…Fluorescence confocal microscopic images revealing expression of hippocampal markers were obtained with a laser scanning microscope (Zeiss 510 Meta). Hippocampal cell culture was performed as described previously (Barry et al, 2008).…”

“…Brains were perfused as above, embedded in paraffin, and sectioned coronally at 6 m. Hematoxylin staining and immunohistochemistry were performed as described previously (Barry et al, 2008).…”

Combined allelic dosage of Nfia and Nfib regulates cortical development

“…Analyses of knockout mouse models suggest that the general underlying cause of these phenotypes is a cellular differentiation defect which affects radial glia, the embryonic neural progenitor cells of the cerebral cortex, which give rise to mature neurons and glia in the cortex (Barry et al, 2008;Betancourt et al, 2014;Gobius et al, 2016;Piper et al, 2009Piper et al, , 2010Piper et al, , 2014. Knockout of either Nfia or Nfib causes the radial glia to remain proliferative and undifferentiated for an extended period of time.…”