No abstract

To identify the fates that astroglial cells can attain in the postnatal brain, we generated mice carrying an inducible Cre recombinase (Cre-ER T2 ) controlled by the human GFAP promoter (hGFAP). In mice carrying the GCE (hGFAP-Cre-ER T2 ) transgene, OHT (4-hydroxytamoxifen) injections induced Cre recombination in astroglial cells at postnatal day 5 and allowed us to permanently tag these cells with reporter genes. Three days after recombination, reporter-tagged cells were quiescent astroglial cells that expressed the stem cell marker LeX in the subventricular zone (SVZ) and dentate gyrus (DG). After 2-4 weeks, the tagged GFAP lineage included proliferating progenitors expressing the neuronal marker Dcx (Doublecortin) in the SVZ and the DG. After 4 weeks, the GFAP lineage generated mature neurons in the olfactory bulb (OB), DG, and, strikingly, also in the cerebral cortex. A major portion of all neurons in the DG and OB born at the end of the first postnatal week were generated from GFAP ϩ cells. In addition to neurons, mature oligodendrocytes and astrocytes populating the cerebral cortex and white matter were also the progeny of GFAP ϩ astroglial ancestors. Thus, genetic fate mapping of postnatal GFAP ϩ cells reveals that they seed the postnatal brain with neural progenitors/stem cells that in turn give rise to neural precursors and their mature neuronal and oligodendrocytic progeny in many CNS regions, including the cerebral cortex.

No abstract

Midline astroglia in the cerebral cortex develop earlier than other astrocytes through mechanisms that are still unknown. We show that radial glia in dorsomedial cortex retract their apical endfeet at midneurogenesis and translocate to the overlaying pia, forming the indusium griseum. These cells require the fibroblast growth factor receptor 1 (Fgfr1) gene for their precocious somal translocation to the dorsal midline, as demonstrated by inactivating the Fgfr1 gene in radial glial cells and by RNAi knockdown of Fgfr1 in vivo. Dysfunctional astroglial migration underlies the callosal dysgenesis in conditional Fgfr1 knockout mice, suggesting that precise targeting of astroglia to the cortex has unexpected roles in axon guidance. FGF signaling is sufficient to induce somal translocation of radial glial cells throughout the cortex; furthermore, the targeting of astroglia to dorsolateral cortex requires FGFr2 signaling after neurogenesis. Hence, FGFs have an important role in the transition from radial glia to astrocytes by stimulating somal translocation of radial glial cells.

Fibroblast growth factor receptor 1 (Fgfr1) is expressed at high levels by progenitor cells of the ventricular zone (VZ) within the hippocampal primordium. To investigate the role of Fgfr1 in these cells, in vivo Cre recombination of "floxed" Fgfr1 alleles was directed to cells of the radial glial lineage by using the human glial fibrillary acidic protein promoter. Radial glial-like cells of the hippocampal VZ are the progenitors of pyramidal neurons and granule cells of hippocampal dentate gyrus (DG). Mice carrying null Fgfr1 alleles (Fgfr1 ⌬flox ) in cells of this lineage showed a dramatic loss of Fgfr1 gene expression throughout the embryonic dorsal telencephalon. These Fgfr1 ⌬flox mice exhibited a ϳ30% decrease in dividing radial glial progenitor cells in the hippocampal VZ and DG in the late embryonic period, progressing to a ϳ50 -60% loss at birth, without any changes in cell survival. In addition, no FGF2-sensitive neural stem cells could be isolated from the Fgfr1 ⌬flox hippocampal neuroepithelium, whereas epidermal growth factor-sensitive neural stem cells were not affected. The number of hippocampal pyramidal neurons and DG granule cells was ϳ30 -50% decreased from the perinatal period through adulthood, and the number of parvalbumin-containing interneurons was similarly decreased in both the DG and pyramidal cell fields. We conclude that Fgfr1 is necessary for hippocampal growth, because it promotes the proliferation of hippocampal progenitors and stem cells during development.