XB-ART-55877
eNeuro
March 1, 2019;
6
(2):
The Expression of Key Guidance Genes at a Forebrain Axon Turning Point Is Maintained by Distinct Fgfr Isoforms but a Common Downstream Signal Transduction Mechanism.
Abstract
During development the axons of neurons grow toward and locate their synaptic partners to form functional neural circuits. Axons do so by reading a map of guidance cues expressed by surrounding tissues. Guidance cues are expressed at a precise space and time, but how guidance cue expression is regulated, and in a coordinated manner, is poorly understood. Semaphorins (Semas) and Slits are families of molecular ligands that guide axons. We showed previously that fibroblast growth factor (Fgf) signaling maintains sema3a and slit1 forebrain expression in Xenopus laevis, and these two repellents cooperate to guide retinal ganglion cell (RGC) axons away from the mid-diencephalon and on towards the optic tectum. Here, we investigate whether there are common features of the regulatory pathways that control the expression of these two guidance cues at this single axon guidance decision point. We isolated the sema3a proximal promoter and confirmed its responsiveness to Fgf signaling. Through misexpression of truncated Fgf receptors (Fgfrs), we found that sema3a forebrain expression is dependent on Fgfr2-4 but not Fgfr1. This is in contrast to slit1, whose expression we showed previously depends on Fgfr1 but not Fgfr2-4. Using pharmacological inhibitors and misexpression of constitutively active (CA) and dominant negative (DN) signaling intermediates, we find that while distinct Fgfrs regulate these two guidance genes, intracellular signaling downstream of Fgfrs appears to converge along the phosphoinositol 3-kinase (PI3K)-Akt signaling pathway. A common PI3K-Akt signaling pathway may allow for the coordinated expression of guidance cues that cooperate to direct axons at a guidance choice point.
PubMed ID: 30993182
PMC ID: PMC6464512
Article link: eNeuro
Species referenced: Xenopus laevis
Genes referenced: actb akt1 dynll1 fgfr1 fgfr2 fgfr3 fgfr4 gab1 grb2 hpse map3k1 mapk1 myc pik3ca pik3cg sdc2 sema3a slit1 slit2 spry1 tec tubb
GO keywords: axon guidance [+]
Antibodies: Akt Ab10 Gapdh Ab4 Mapk1 Ab7 Sema3a Ab1
Article Images: [+] show captions
References [+] :
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2012, Pubmed
Aksamitiene,
Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance.
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Pubmed
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Atkinson-Leadbeater, FGF receptor dependent regulation of Lhx9 expression in the developing nervous system. 2009, Pubmed , Xenbase
Belgacem, Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. 2011, Pubmed , Xenbase
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Bertolesi, Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus. 2012, Pubmed , Xenbase
Blondeau, Dual leucine zipper kinase regulates expression of axon guidance genes in mouse neuronal cells. 2017, Pubmed
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Browaeys-Poly, Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation. 2010, Pubmed , Xenbase
Campbell, Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. 2001, Pubmed , Xenbase
Casar, ERK Signals: Scaffolding Scaffolds? 2016, Pubmed
Chen, BRAFV600E negatively regulates the AKT pathway in melanoma cell lines. 2013, Pubmed
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Choi, And Akt-ion! IQGAP1 in control of signaling pathways. 2018, Pubmed
Choi, IQGAP1 is a phosphoinositide effector and kinase scaffold. 2017, Pubmed
Chédotal, The brain within the tumor: new roles for axon guidance molecules in cancers. 2005, Pubmed
Dailey, Mechanisms underlying differential responses to FGF signaling. 2005, Pubmed
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Dickson, Molecular mechanisms of axon guidance. 2003, Pubmed
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Jimenez, The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. 2003, Pubmed
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Kita, Neuropilin-1 biases dendrite polarization in the retina. 2013, Pubmed , Xenbase
Klint, Signal transduction by fibroblast growth factor receptors. 1999, Pubmed
Klint, Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells. 1995, Pubmed
Law, The role of semaphorins and their receptors in gliomas. 2012, Pubmed
Lemmon, Cell signaling by receptor tyrosine kinases. 2010, Pubmed
Luukko, Integration of tooth morphogenesis and innervation by local tissue interactions, signaling networks, and semaphorin 3A. 2017, Pubmed
Manning, AKT/PKB signaling: navigating downstream. 2007, Pubmed
Marín, Guiding neuronal cell migrations. 2010, Pubmed
Meister, Mitogen-Activated Protein (MAP) Kinase Scaffolding Proteins: A Recount. 2013, Pubmed
Mendoza, The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. 2011, Pubmed
Musci, Regulation of the fibroblast growth factor receptor in early Xenopus embryos. 1990, Pubmed , Xenbase
Nakamura, Regulation and physiological functions of mammalian phospholipase C. 2017, Pubmed
Nakayama, FGF induces oscillations of Hes1 expression and Ras/ERK activation. 2008, Pubmed
O'Donnell, Axon growth and guidance: receptor regulation and signal transduction. 2009, Pubmed
Ornitz, The Fibroblast Growth Factor signaling pathway. 2016, Pubmed
Palmada, The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid transporter ASCT2. 2005, Pubmed , Xenbase
Pudney, Establishment of a cell line (XTC-2) from the South African clawed toad, Xenopus laevis. 1973, Pubmed , Xenbase
Raffioni, Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. 1999, Pubmed
Reidy, Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk. 2011, Pubmed
Rodriguez-Viciana, Phosphatidylinositol-3-OH kinase as a direct target of Ras. 1994, Pubmed
Roth, The many faces of semaphorins: from development to pathology. 2009, Pubmed
Roy, IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. 2005, Pubmed
Rubinfeld, The ERK cascade as a prototype of MAPK signaling pathways. 2004, Pubmed
Schneider, NIH Image to ImageJ: 25 years of image analysis. 2012, Pubmed
Seiradake, Structural Perspectives on Axon Guidance. 2017, Pubmed
Selvaraj, Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation. 2014, Pubmed
Shaoul, Fibroblast growth factor receptors display both common and distinct signaling pathways. 1995, Pubmed
Sitaras, Retinal neurons curb inflammation and enhance revascularization in ischemic retinopathies via proteinase-activated receptor-2. 2015, Pubmed
Stulberg, Crosstalk between Fgf and Wnt signaling in the zebrafish tailbud. 2012, Pubmed
Tachibana, Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling. 2017, Pubmed
Ueno, A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. 1992, Pubmed , Xenbase
Vainikka, Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. 1994, Pubmed
Vergara, Retinal regeneration in the Xenopus laevis tadpole: a new model system. 2009, Pubmed , Xenbase
Wang, Fibroblast growth factor receptors have different signaling and mitogenic potentials. 1994, Pubmed
Webber, Multiple signaling pathways regulate FGF-2-induced retinal ganglion cell neurite extension and growth cone guidance. 2005, Pubmed , Xenbase
Westfall, Requirement for intracellular calcium modulation in zebrafish dorsal-ventral patterning. 2003, Pubmed
Wiedemann, Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. 2001, Pubmed
Yang, Fibroblast growth factor receptor 1 signaling transcriptionally regulates the axon guidance cue slit1. 2018, Pubmed , Xenbase
Yazdani, The semaphorins. 2006, Pubmed
Zimmermann, Phosphorylation and regulation of Raf by Akt (protein kinase B). 1999, Pubmed
de Ramon Francàs, The spinal cord shows the way - How axons navigate intermediate targets. 2017, Pubmed
Alessi, Mechanism of activation and function of protein kinase B. 1998, Pubmed
Alessi, Mechanism of activation of protein kinase B by insulin and IGF-1. 1997, Pubmed
Atkinson-Leadbeater, Dynamic expression of axon guidance cues required for optic tract development is controlled by fibroblast growth factor signaling. 2010, Pubmed , Xenbase
Atkinson-Leadbeater, Fgfr signaling is required as the early eye field forms to promote later patterning and morphogenesis of the eye. 2014, Pubmed , Xenbase
Atkinson-Leadbeater, FGF receptor dependent regulation of Lhx9 expression in the developing nervous system. 2009, Pubmed , Xenbase
Belgacem, Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. 2011, Pubmed , Xenbase
Ben Messaoud, Osmostress-induced apoptosis in Xenopus oocytes: role of stress protein kinases, calpains and Smac/DIABLO. 2016, Pubmed , Xenbase
Bertolesi, Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus. 2012, Pubmed , Xenbase
Blondeau, Dual leucine zipper kinase regulates expression of axon guidance genes in mouse neuronal cells. 2017, Pubmed
Boehm, Integrative genomic approaches identify IKBKE as a breast cancer oncogene. 2007, Pubmed
Browaeys-Poly, Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation. 2010, Pubmed , Xenbase
Campbell, Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. 2001, Pubmed , Xenbase
Casar, ERK Signals: Scaffolding Scaffolds? 2016, Pubmed
Chen, BRAFV600E negatively regulates the AKT pathway in melanoma cell lines. 2013, Pubmed
Chen, IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. 2010, Pubmed
Chen, Targeting of retinal axons requires the metalloproteinase ADAM10. 2007, Pubmed , Xenbase
Chien, Navigational errors made by growth cones without filopodia in the embryonic Xenopus brain. 1993, Pubmed , Xenbase
Choi, And Akt-ion! IQGAP1 in control of signaling pathways. 2018, Pubmed
Choi, IQGAP1 is a phosphoinositide effector and kinase scaffold. 2017, Pubmed
Chédotal, The brain within the tumor: new roles for axon guidance molecules in cancers. 2005, Pubmed
Dailey, Mechanisms underlying differential responses to FGF signaling. 2005, Pubmed
Das, Releasing prophase arrest in zebrafish oocyte: synergism between maturational steroid and Igf1. 2016, Pubmed
Dickson, Molecular mechanisms of axon guidance. 2003, Pubmed
Feiner, Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. 2001, Pubmed
Fenstermaker, Regulation of dendritic length and branching by semaphorin 3A. 2004, Pubmed
Friesel, cDNA cloning and developmental expression of fibroblast growth factor receptors from Xenopus laevis. 1991, Pubmed , Xenbase
Fujisawa, Discovery of semaphorin receptors, neuropilin and plexin, and their functions in neural development. 2004, Pubmed , Xenbase
Fukuchi-Shimogori, Neocortex patterning by the secreted signaling molecule FGF8. 2001, Pubmed
Goetz, Exploring mechanisms of FGF signalling through the lens of structural biology. 2013, Pubmed
Golub, Evolutionarily conserved and divergent expression of members of the FGF receptor family among vertebrate embryos, as revealed by FGFR expression patterns in Xenopus. 2001, Pubmed , Xenbase
Haas, Targeted electroporation in Xenopus tadpoles in vivo--from single cells to the entire brain. 2003, Pubmed , Xenbase
Hacohen, sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. 1998, Pubmed
Hemmings, PI3K-PKB/Akt pathway. 2013, Pubmed
Holt, A single-cell analysis of early retinal ganglion cell differentiation in Xenopus: from soma to axon tip. 1989, Pubmed , Xenbase
Jiang, Differential actions of fibroblast growth factors on intracellular pathways and target gene expression in bovine ovarian granulosa cells. 2013, Pubmed
Jiang, Fibroblast growth factor-2 regulation of Sprouty and NR4A genes in bovine ovarian granulosa cells. 2011, Pubmed
Jimenez, The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. 2003, Pubmed
Jin, Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt. 2015, Pubmed , Xenbase
Kagoshima, Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis. 2001, Pubmed
Kanai, Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein. 1997, Pubmed
Kita, Neuropilin-1 biases dendrite polarization in the retina. 2013, Pubmed , Xenbase
Klint, Signal transduction by fibroblast growth factor receptors. 1999, Pubmed
Klint, Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells. 1995, Pubmed
Law, The role of semaphorins and their receptors in gliomas. 2012, Pubmed
Lemmon, Cell signaling by receptor tyrosine kinases. 2010, Pubmed
Luukko, Integration of tooth morphogenesis and innervation by local tissue interactions, signaling networks, and semaphorin 3A. 2017, Pubmed
Manning, AKT/PKB signaling: navigating downstream. 2007, Pubmed
Marín, Guiding neuronal cell migrations. 2010, Pubmed
Meister, Mitogen-Activated Protein (MAP) Kinase Scaffolding Proteins: A Recount. 2013, Pubmed
Mendoza, The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. 2011, Pubmed
Musci, Regulation of the fibroblast growth factor receptor in early Xenopus embryos. 1990, Pubmed , Xenbase
Nakamura, Regulation and physiological functions of mammalian phospholipase C. 2017, Pubmed
Nakayama, FGF induces oscillations of Hes1 expression and Ras/ERK activation. 2008, Pubmed
O'Donnell, Axon growth and guidance: receptor regulation and signal transduction. 2009, Pubmed
Ornitz, The Fibroblast Growth Factor signaling pathway. 2016, Pubmed
Palmada, The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid transporter ASCT2. 2005, Pubmed , Xenbase
Pudney, Establishment of a cell line (XTC-2) from the South African clawed toad, Xenopus laevis. 1973, Pubmed , Xenbase
Raffioni, Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. 1999, Pubmed
Reidy, Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk. 2011, Pubmed
Rodriguez-Viciana, Phosphatidylinositol-3-OH kinase as a direct target of Ras. 1994, Pubmed
Roth, The many faces of semaphorins: from development to pathology. 2009, Pubmed
Roy, IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. 2005, Pubmed
Rubinfeld, The ERK cascade as a prototype of MAPK signaling pathways. 2004, Pubmed
Schneider, NIH Image to ImageJ: 25 years of image analysis. 2012, Pubmed
Seiradake, Structural Perspectives on Axon Guidance. 2017, Pubmed
Selvaraj, Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation. 2014, Pubmed
Shaoul, Fibroblast growth factor receptors display both common and distinct signaling pathways. 1995, Pubmed
Sitaras, Retinal neurons curb inflammation and enhance revascularization in ischemic retinopathies via proteinase-activated receptor-2. 2015, Pubmed
Stulberg, Crosstalk between Fgf and Wnt signaling in the zebrafish tailbud. 2012, Pubmed
Tachibana, Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling. 2017, Pubmed
Ueno, A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. 1992, Pubmed , Xenbase
Vainikka, Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. 1994, Pubmed
Vergara, Retinal regeneration in the Xenopus laevis tadpole: a new model system. 2009, Pubmed , Xenbase
Wang, Fibroblast growth factor receptors have different signaling and mitogenic potentials. 1994, Pubmed
Webber, Multiple signaling pathways regulate FGF-2-induced retinal ganglion cell neurite extension and growth cone guidance. 2005, Pubmed , Xenbase
Westfall, Requirement for intracellular calcium modulation in zebrafish dorsal-ventral patterning. 2003, Pubmed
Wiedemann, Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. 2001, Pubmed
Yang, Fibroblast growth factor receptor 1 signaling transcriptionally regulates the axon guidance cue slit1. 2018, Pubmed , Xenbase
Yazdani, The semaphorins. 2006, Pubmed
Zimmermann, Phosphorylation and regulation of Raf by Akt (protein kinase B). 1999, Pubmed
de Ramon Francàs, The spinal cord shows the way - How axons navigate intermediate targets. 2017, Pubmed