DOI: 10.1126/science.1064252. Neocortex Patterning by the Secreted Signaling Molecule FGF8

Neocortex Patterning by the Secreted Signaling Molecule FGF8

10.1126/science.1064252

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

A classic model proposes that the mammalian neocortex is divided into areas early in neurogenesis, but the molecular mechanisms that generate the area map have been elusive. Here we provide evidence that FGF8 regulates development of the map from a source in the anterior telencephalon. Using electroporation-mediated gene transfer in mouse embryos, we show that augmenting the endogenous anterior FGF8 signal shifts area boundaries posteriorly, reducing the signal shifts them anteriorly, and introducing a posterior source of FGF8 elicits partial area duplications, revealed by ectopic somatosensory barrel fields. These findings support a role for FGF signaling in specifying positional identity in the neocortex.

Bibliography

Fukuchi-Shimogori, T., & Grove, E. A. (2001). Neocortex Patterning by the Secreted Signaling Molecule FGF8. Science, 294(5544), 1071â1074.

Authors 2

Tomomi Fukuchi-Shimogori (first)
Elizabeth A. Grove (additional)

References 44 Referenced 581

W. J. H. Nauta M. Feirtag Fundamental Neuroanatomy (Freeman New York 1986).
10.1126/science.3291116
P. Levitt M. F. Barbe K. L. Eagleson in Annual Review of Neuroscience W. M. Cowan Ed. (Annual Reviews Palo Alto CA 1997) vol. 20 p. 1. (10.1146/annurev.neuro.20.1.1)
J. L. R. Rubenstein et al. Cereb. Cortex 9 524 (1999). (10.1093/cercor/9.6.524)
10.1126/science.285.5429.906
10.1126/science.288.5464.344
10.1016/S0959-4388(00)00173-2
10.1242/dev.121.2.439
10.1242/dev.124.11.2203
10.1242/dev.124.14.2709
10.1242/dev.125.12.2315
10.1038/380066a0
10.1016/S0092-8674(00)80333-5
10.1016/S0092-8674(00)81437-3
H. Shamim et al. Development 126 945 (1999). (10.1242/dev.126.5.945)
10.1242/dev.126.1.51
10.1016/0925-4773(94)90022-1
C. W. Ragsdale et al. unpublished observations.
10.1046/j.1440-169x.2000.00502.x
10.1126/science.1058624
K. J. Huffman et al. J. Neurosci 19 9939 (1999). (10.1523/JNEUROSCI.19-22-09939.1999)
10.1523/JNEUROSCI.19-12-04889.1999
10.1523/JNEUROSCI.11-02-00519.1991
10.1093/cercor/9.6.601
10.1006/mcne.1997.0626
MacArthur C. A., et al., Cell Growth Differ. 6, 817 (1995). / Cell Growth Differ. by MacArthur C. A. (1995)
10.1242/dev.124.5.959
10.1242/dev.127.9.1833
10.1242/dev.127.3.457
10.1074/jbc.274.49.34785
C. A. MacArthur et al. Development 121 3603 (1995). (10.1242/dev.121.11.3603)
T. Fukuchi-Shimogori E. A. Grove unpublished observations.
10.1016/0006-8993(70)90079-X
10.1126/science.179.4071.395
10.1523/JNEUROSCI.07-11-03529.1987
10.1242/dev.121.4.1151
10.1242/dev.127.3.469
Timed-pregnant CD-1 mice were obtained from the University of Chicago Cancer Research Center Transgenic Facility. Noon of the day on which a vaginal plug is seen is termed E0.5. Animal care was according to institutional guidelines.
The expression vector backbone was pEF1/Myc-His C (Invitrogen) with gene expression driven from the human elongation factor 1α promoter enhancer. A 2.2-kb fragment between Pvu II sites containing neomycin and SV40 elements was removed to reduce plasmid size generating pEFX (20). Complementary DNAs encoding mouse FGF8 isoform b mouse WNT3a human placental alkaline phosphatase (AP) or a truncated soluble human FGFR3c (sFGFR3) were inserted into pEFX. sFGFR3 was generated with 5′-GCCATGGGCGCCCCTGCCTGCGCCCTCGC-3′ and 3′-TCGGGGGGGTTCTTTCCGGACCCGAGGATT-5′ polymerase chain reaction primers and encodes the extracellular portion of FGFR3c.
Analysis of 295 AP -electroporated cortical hemispheres with gene expression morphological cell proliferation or cell death assays indicates that electroporation under our conditions does not itself disrupt neocortical development.
G. Minowada et al. Development 126 4465 (1999). (10.1242/dev.126.20.4465)
Most electroporated brains required analysis at P0 or P6 several days after transient ectopic gene expression could be directly detected. To determine the frequency of effective gene transfection several litters were electroporated at E11.5 with Fgf8 or AP plasmids and harvested 48 hours later. Half of the surviving embryos in each litter showed strong transgene expression (31/60). Consistent with this observation shifts in area domains (Figs. 2 to 4) were seen at P0 or P6 in about one-half of the mice electroporated with Fgf8 or sFGFR3 at E11.5 ( n = 56/108 with 52 brains showing no shifts). Shifts were invariably consistent i.e. in the posterior direction for anterior FGF8 overexpression and in the anterior direction for presumed FGF inhibition. No shifts were seen in mice electroporated with the AP control plasmid ( n = 0/51). Ectopic S1 barrels (Fig. 5) appeared in 10/37 P6 brains after posterior electroporation of Fgf8. This lower frequency of effect may be due to the greater difficulty of successful posterior electroporation. Ectopic S1 barrels were not seen after posterior electroporation of AP ( n = 0/24).
10.1073/pnas.77.4.2333
We thank S. Agarwala S. Assimacopoulos P. Mason C. W. Ragsdale T. Sanders and C. S. Wellek for discussion and technical help and advice and C. MacArthur A. McMahon G. Martin S. McConnell M. Donoghue M. Takeichi M. J. Hayman and A. Rattner for cDNAs. Supported by NIH and the March of Dimes Birth Defects Foundation.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:35 a.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 5:52 p.m.)
Indexed	4 days, 7 hours ago (Aug. 28, 2025, 8:36 a.m.)
Issued	23 years, 9 months ago (Nov. 2, 2001)
Published	23 years, 9 months ago (Nov. 2, 2001)
Published Print	23 years, 9 months ago (Nov. 2, 2001)

Funders 0

None

BibTeX

@article{Fukuchi_Shimogori_2001, title={Neocortex Patterning by the Secreted Signaling Molecule FGF8}, volume={294}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1064252}, DOI={10.1126/science.1064252}, number={5544}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Fukuchi-Shimogori, Tomomi and Grove, Elizabeth A.}, year={2001}, month=nov, pages={1071–1074} }

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