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      FGFs: Neurodevelopment’s Jack-of-all-Trades – How Do They Do it?

      review-article
      1 , 2
      Frontiers in Neuroscience
      Frontiers Research Foundation
      FGF, neural patterning, cell survival, neurogenesis, telencephalon, neocortex

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          Abstract

          From neurulation to postnatal processes, the requirements for FGF signaling in many aspects of neural precursor cell biology have been well documented. However, identifying a requirement for FGFs in a particular neurogenic process provides only an initial and superficial understanding of what FGF signaling is doing. How FGFs specify cell types in one instance, yet promote cell survival, proliferation, migration, or differentiation in other instances remains largely unknown and is key to understanding how they function. This review describes what we have learned primarily from in vivo vertebrate studies about the roles of FGF signaling in neurulation, anterior–posterior patterning of the neural plate, brain patterning from local signaling centers, and finally neocortex development as an example of continued roles for FGFs within the same brain area. The potential explanations for the diverse functions of FGFs through differential interactions with cell intrinsic and extrinsic factors is then discussed with an emphasis on how little we know about the modulation of FGF signaling in vivo. A clearer picture of the mechanisms involved is nevertheless essential to understand the behavior of neural precursor cells and to potentially guide their fates for therapeutic purposes.

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          Most cited references149

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          Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.

          In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1-9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10-23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity.
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            Evolution of the Fgf and Fgfr gene families.

            Fibroblast growth factors (Fgfs) and Fgf receptors (Fgfrs) comprise a signaling system that is conserved throughout metazoan evolution. Twenty-two Fgfs and four Fgfrs have been identified in humans and mice. During evolution, the Fgf family appears to have expanded in two phases. In the first phase, during early metazoan evolution, Fgfs expanded from two or three to six genes by gene duplication. In the second phase, during the evolution of early vertebrates, the Fgf family expanded by two large-scale gen(om)e duplications. By contrast, the Fgfr family has expanded only in the second phase. However, the acquisition of alternative splicing by Fgfrs has increased their functional diversity. The mechanisms that regulate alternative splicing have been conserved since the divergences of echinoderms and vertebrates. The expansion of the Fgf and Fgfr gene families has enabled this signaling system to acquire functional diversity and, therefore, an almost ubiquitous involvement in developmental and physiological processes.
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              Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal.

              BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.
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                Author and article information

                Journal
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Research Foundation
                1662-4548
                1662-453X
                05 December 2011
                2011
                : 5
                : 133
                Affiliations
                [1] 1simpleDepartment of Neuroscience, Albert Einstein College of Medicine Bronx, NY, USA
                [2] 2simpleDepartment of Genetics, Albert Einstein College of Medicine Bronx, NY, USA
                Author notes

                Edited by: Nicholas Gaiano, Johns Hopkins School of Medicine, USA

                Reviewed by: Maria J. Donoghue, Georgetown University, USA; Umberto Di Porzio, Institute of Genetics and Biophysics, Italy

                *Correspondence: Jean M. Hébert, Department of Neuroscience, Albert Einstein College of Medicine, Kennedy Building, 1410 Pelham Parkway South, Bronx, NY 10461, USA. e-mail: jean.hebert@ 123456einstein.yu.edu

                This article was submitted to Frontiers in Neurogenesis, a specialty of Frontiers in Neuroscience.

                Article
                10.3389/fnins.2011.00133
                3230033
                22164131
                8beb3516-a05b-47e0-812b-3352e9693ebf
                Copyright © 2011 Hébert.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 05 June 2011
                : 18 November 2011
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 159, Pages: 10, Words: 10448
                Categories
                Neuroscience
                Review Article

                Neurosciences
                neocortex,telencephalon,fgf,neural patterning,cell survival,neurogenesis
                Neurosciences
                neocortex, telencephalon, fgf, neural patterning, cell survival, neurogenesis

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