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Midline radial glia translocation and corpus callosum formation require FGF signaling

Nature Neuroscience volume 9, pages 787–797 (2006)Cite this article

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.

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Figure 1: Disruption of dorsal telencephalic commissures in glial-specific Fgfr1 mutant mice and enriched expression of FGF-related genes in anterior midline.
Figure 2: Normal corpus callosum and midline glia in mice lacking Fgfr1 in neurons.
Figure 3: Migration of astroglial cells to the indusium griseum is disrupted in glial-specific Fgfr1 mutant.
Figure 4: Midline radial glia translocation is absent in glial-specific Fgfr1 mutant embryos.
Figure 5: Cell-autonomous regulation of midline radial glia translocation by FGF signaling.
Figure 6: FGF signaling is sufficient to induce premature radial glial cell translocation in developing cortex.
Figure 7: Fgfr2 is required for astroglial targeting to the dorsolateral cortex (a–c) BLBP staining in control (a), Fgfr2f/f;hGFAPCre (b) and Fgfr1;Fgfr2f/f;hGFAPCre (c) E18.5 embryos, showing normal radial glial morphology in Fgfr2 single and Fgfr1/Fgfr2 double mutant mice.

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Acknowledgements

We thank A. Uchida for explant preparation and valuable discussions; S.L. Ellis and J. Silbereis for technical assistance; R. Slack (University of Ottawa, Ottawa, Ontario) for the Nestin-Cre mice; J. Marth (University of California San Diego) for the SynI-Cre mice; J. Partanen (Institute of Biotechnology, University of Helsinki, Helsinki, Finland) for the FGFr1f/f mice; D. Ornitz (Washington University Medical School, Saint Louis) for the FGFr2f/f mice; K. Kwan (Yale University, New Haven) for generating pCGLH; E. Anton (University of North Carolina, Chapel Hill, North Carolina) for providing pBLBP-EGFP; and J. Miyazaki (Osaka University, Osaka, Japan) for providing pCAGGS. We are grateful to M. Tessier-Lavigne (Genentech, South San Francisco) for probes and J. Rubenstein (University of California San Francisco) for sharing data. This work was supported by the US National Institutes of Health (grants MH067715, NS35476, 5T32-MH18268, NS054273 and HD045481) and the National Alliance for Research on Schizophrenia and Depression Foundation.

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  1. Karen Müller Smith and Yasushi Ohkubo: These authors contributed equally to this work.

Authors and Affiliations

  1. Child Study Center, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Karen Müller Smith, Yasushi Ohkubo, Maria Elisabetta Maragnoli & Flora M Vaccarino

  2. Department of Neurobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Mladen-Roko Rašin, Michael L Schwartz, Nenad Šestan & Flora M Vaccarino

  3. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Mladen-Roko Rašin & Nenad Šestan

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Supplementary information

Supplementary Fig. 1

Lack of dorsal telencephalic commissures in Fgfr1 mutants correlates with absence of the IG. (PDF 1564 kb)

Supplementary Fig. 2

Fgfr1 mutants have specific deficits in the formation of dorsal telencephalic commissures. (PDF 706 kb)

Supplementary Fig. 3

Fgfr1 mutation does not alter the expression of neuronal factors implicated in midline axon guidance. (PDF 487 kb)

Supplementary Fig. 4

In situ hybridization and RT-PCR of axon guidance molecules in control and hGfap/Cre Fgfr1 mutant embryos. (PDF 497 kb)

Supplementary Fig. 5

Decreased expression of Fgfr1 protein after shRNA knockdown and Fgfr2 mRNA in Fgfr2f/f;hGfapCre mice. (PDF 573 kb)

Supplementary Methods (PDF 107 kb)

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Smith, K., Ohkubo, Y., Maragnoli, M. et al. Midline radial glia translocation and corpus callosum formation require FGF signaling. Nat Neurosci 9, 787–797 (2006). https://doi.org/10.1038/nn1705

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