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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.

SUBMITTER: Toyoda R

PROVIDER: S-EPMC2947756 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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FGF8 acts as a classic diffusible morphogen to pattern the neocortex.

Toyoda Reiko R Assimacopoulos Stavroula S Wilcoxon Jennifer J Taylor Albert A Feldman Polina P Suzuki-Hirano Asuka A Shimogori Tomomi T Grove Elizabeth A EA

Development (Cambridge, England) 20100915 20

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 dir ...[more]

PMID: 20843859

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Project description:Fibroblast growth factor (FGF) morphogen signalling through the evolutionarily ancient extracellular signalling-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway recurs in many neural and non-neural developmental contexts, and understanding the mechanisms that regulate FGF/ERK function are correspondingly important. The glycosaminoglycan heparan sulphate (HS) binds to FGFs and exists in an enormous number of differentially sulphated forms produced by the action of HS modifying enzymes, and so has the potential to present an extremely large amount of information in FGF/ERK signalling. Although there have been many studies demonstrating that HS is an important regulator of FGF function, experimental evidence on the role of the different HS modifying enzymes on FGF gradient formation has been lacking until now. We challenged ex vivo developing mouse neural tissue, in which HS had either been enzymatically removed by heparanase treatment or lacking either the HS modifying enzymes Hs2st (Hs2st-/- tissue) or Hs6st1 (Hs6st1-/- tissue), with exogenous Fgf8 to gain insight on how HS and the function of these two HS modifying enzymes impacts on Fgf8 gradient formation from an exogenously supplied source of Fgf8 protein. We discover that two different HS modifying enzymes, Hs2st and Hs6st1, indeed differentially modulate the properties of emerging Fgf8 protein concentration gradients and the Erk signalling output in response to Fgf8 in living tissue in ex vivo cultures. Both Hs2st and Hs6st1 are required for stable Fgf8 gradients to form as rapidly as they do in wild-type tissue while only Hs6st1 has a significant effect on suppressing the levels of Fgf8 protein in the gradient compared to wild type. Next we show that Hs2st and Hs6st1 act to antagonise and agonise the Erk signalling in response to Fgf8 protein, respectively, in ex vivo cultures of living tissue. Examination of endogenous Fgf8 protein and Erk signalling outputs in Hs2st-/- and Hs6st1-/- embryos suggests that our ex vivo findings have physiological relevance in vivo Our discovery identifies a new class of mechanism to tune Fgf8 function by regulated expression of Hs2st and Hs6st1 that is likely to have broader application to the >200 other signalling proteins that interact with HS and their function in neural development and disease.

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FGF8 acts as a classic diffusible morphogen to pattern the neocortex.

Publications

FGF8 acts as a classic diffusible morphogen to pattern the neocortex.

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