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Specification of dorsal telencephalic character by sequential Wnt and FGF signaling

Nature Neuroscience volume 6, pages 701–707 (2003)Cite this article

Abstract

Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.

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Figure 1: Domains of expression of transcription factors define ventral, intermediate and dorsal subdivisions of the developing telencephalon.
Figure 2: Telencephalic cells gradually acquire dorsal character.
Figure 3: Signals derived from the dorsal epidermal ectoderm could induce dorsal telencephalic character in prospective ventral telencephalic cells.
Figure 4: Wnt3A induces dorsal character in prospective ventral telencephalic cells in a concentration-dependent manner.
Figure 5: Wnt and FGF activity are required to induce dorsal character in prospective dorsal telencephalic cells.
Figure 6: The temporal expression of Fgf8 in the developing forebrain controls the generation of telencephalic cells of definitive dorsal character.

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Acknowledgements

We thank D. Anderson, P. Brickell, G. Corte, K. Campbell, J. Nathans and A. Streit for kindly providing us antibodies, plasmids and cell lines. We are grateful to members of the Edlund lab for discussions. T.E. is supported by the Swedish Medical Research Council, the Foundation for Strategic Research and the European Union research programs. T.M.J. is supported by grants from the National Institute of Neurological Disorders and Stroke and is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Umeå Center for Molecular Medicine, Building 6M, 4th floor, Umeå University, Umeå, S-901 87, Sweden

    Lena Gunhaga, Matthew Marklund, My Sjödal & Thomas Edlund

  2. Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, 11794, New York, USA

    Jen-Chih Hsieh

  3. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, 10032, New York, USA

    Thomas M Jessell

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Correspondence to Thomas Edlund.

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Supplementary information

Supplementary Fig. 1.

BMP is not required for the specification of dorsal telencephalic Pax6+and Emx1+ cells. At stage 8,Bmp4 is expressed in the neural folds flanking the prospective dorsal telencephalon and by stage 10 Bmp4 is expressed in the epidermal ectoderm surrounding the prospective dorsal telencephalon. Expression of transcription factors in stage 8 D-nf explants cultured alone or with Noggin for 52-56 hrs.Stage 8 D-nf explants (n =15)generate Pax6+ cells (72 ± 4%)and Emx1+ cells (>90%)but no Nkx2.1+ or Meis2+ cells. In the presence of Noggin, stage 8 D-nf explants (n =15)still generate Pax6+ cells (66 ± 4%%)and Emx1 + cells (>90%)and no Nkx2.1+or Meis2 + cells were detected. (JPG 65 kb)

Supplementary Fig. 2.

Model of the initial dorsoventral patterning of the telencephalon. (a )A schematic representation showing when cells in different regions of the prospective telencephalon become exposed to Shh,Wnt and FGF signals to acquire their ventral and dorsal character. At stage 8 and 10, cells fated to generate ventral and dorsal regions of the telencephalon are located at different positions along the rostrocaudal axis of the anterior prosencephalon 33-35. For simplicity, however, the dorsoventral axis of the prospective telencephalon is schematically indicated at the same rostrocaudal level. At the neural plate stage (stage 4), all prospective telencephalic cells are exposed to Shh signals and become in response to Shh activity initially specified as ventral/MGE cells. Prospective ventral telencephalic cells maintain their ventral character during development. During neural tube closure (stage 8), Wnt1 and Wnt4 are expressed in the epidermal ectodermal component of the neural folds located adjacent to the prospective dorsal telencephalon and Fgf8 is expressed in the anterior neural ridge (ANR)that abuts prospective ventral but not prospective dorsal telencephalic cells. Soon after neural tube closure (stage 10),Wnt8b is expressed in the dorsal region of the prospective telencephalon,and the expression of Fgf8 has spread dorsally to include cells of the dorsal midline of the prospective dorsal telencephalon and the overlying epidermal ectoderm. (b )Proposed signaling pathways for the induction of telencephalic cells of early dorsal character. Wnt signaling blocks Shh signaling, and prospective dorsal telencephalic cells that are exposed to Wnt activity become specified as early dorsal Pax6+/Ngn2+ cells independent of FGF signaling. Sequential Wnt and FGF activity induces later definitive dorsal Emx1 + telencephalic cells. The specification of the most dorsal midline cells of the telencephalon appears to require both BMP and FGF signaling 15,23,24 , but is not indicated in the model. (JPG 32 kb)

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Gunhaga, L., Marklund, M., Sjödal, M. et al. Specification of dorsal telencephalic character by sequential Wnt and FGF signaling. Nat Neurosci 6, 701–707 (2003). https://doi.org/10.1038/nn1068

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