title: FGF8 acts as a classic diffusible morphogen to pattern the neocortex.
abstract: Gain- and loss-of-function experiments have demonstrated that a source of fibroblast growth factor (FGF) 8 regulates anterior to posterior (A/P) patterning in the neocortical area map. Whether FGF8 controls patterning as a classic diffusible morphogen has not been directly tested. We report evidence that FGF8 diffuses through the mouse neocortical primordium from a discrete source in the anterior telencephalon, forms a protein gradient across the entire A/P extent of the primordium, and acts directly at a distance from its source to determine area identity. FGF8 immunofluorescence revealed FGF8 protein distributed in an A/P gradient. Fate-mapping experiments showed that outside the most anterior telencephalon, neocortical progenitor cells did not express Fgf8, nor were they derived from Fgf8-expressing cells, suggesting that graded distribution of FGF8 results from protein diffusion from the anterior source. Supporting this conclusion, a dominant-negative high-affinity FGF8 receptor captured endogenous FGF8 at a distance from the FGF8 source. New FGF8 sources introduced by electroporation showed haloes of FGF8 immunofluorescence indicative of FGF8 diffusion, and surrounding cells reacted to a new source of FGF8 by upregulating different FGF8-responsive genes in concentric domains around the source. Reducing endogenous FGF8 with the dominant-negative receptor in the central neocortical primordium induced cells to adopt a more posterior area identity, demonstrating long-range area patterning by FGF8. These observations support FGF8 as a classic diffusible morphogen in neocortex, thereby guiding future studies of neocortical pattern formation.
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Toyoda
authors.forename: Stavroula
authors.initials: S
authors.lastname: Assimacopoulos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilcoxon
authors.forename: Albert
authors.initials: A
authors.lastname: Taylor
authors.forename: Polina
authors.initials: P
authors.lastname: Feldman
authors.forename: Asuka
authors.initials: A
authors.lastname: Suzuki-Hirano
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grove
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D019521:Body Patterning / Q000502:physiology*; D018274:Electroporation; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018613:Microscopy, Confocal; D019579:Neocortex / Q000196:embryology* / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C496457:Fgf8 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D051524:Fibroblast Growth Factor 8