PMC:2944667 / 9016-14080 JSONTXT

{"project":"TEST0","denotations":[{"id":"20877431-231-239-637125","span":{"begin":958,"end":962},"obj":"[\"11057895\"]"},{"id":"20877431-232-240-637126","span":{"begin":1749,"end":1753},"obj":"[\"7482802\"]"},{"id":"20877431-233-241-637127","span":{"begin":1762,"end":1766},"obj":"[\"7482803\"]"},{"id":"20877431-191-199-637128","span":{"begin":2242,"end":2246},"obj":"[\"7050307\"]"},{"id":"20877431-134-142-637129","span":{"begin":2383,"end":2387},"obj":"[\"11217860\"]"},{"id":"20877431-211-219-637130","span":{"begin":2796,"end":2800},"obj":"[\"18075251\"]"},{"id":"20877431-188-196-637131","span":{"begin":2991,"end":2995},"obj":"[\"18794345\"]"},{"id":"20877431-208-216-637132","span":{"begin":3011,"end":3015},"obj":"[\"18940588\"]"},{"id":"20877431-230-238-637133","span":{"begin":3374,"end":3378},"obj":"[\"8439411\"]"},{"id":"20877431-217-225-637134","span":{"begin":3598,"end":3602},"obj":"[\"10195217\"]"},{"id":"20877431-177-185-637135","span":{"begin":3782,"end":3786},"obj":"[\"10864959\"]"},{"id":"20877431-198-206-637136","span":{"begin":3803,"end":3807},"obj":"[\"11826116\"]"},{"id":"20877431-212-220-637137","span":{"begin":4022,"end":4026},"obj":"[\"10864959\"]"},{"id":"20877431-182-190-637138","span":{"begin":4336,"end":4340},"obj":"[\"11567107\"]"},{"id":"20877431-202-210-637139","span":{"begin":4356,"end":4360},"obj":"[\"12642494\"]"},{"id":"20877431-222-230-637140","span":{"begin":4376,"end":4380},"obj":"[\"16613831\"]"},{"id":"20877431-82-90-637141","span":{"begin":4465,"end":4469},"obj":"[\"18625063\"]"},{"id":"20877431-222-230-637142","span":{"begin":4736,"end":4740},"obj":"[\"12915315\"]"},{"id":"20877431-234-242-637143","span":{"begin":4758,"end":4762},"obj":"[\"18625063\"]"}],"text":"FGF ligands, stem cell amplification and cortical neurogenesis\nFibroblast growth factor ligands are peptides that act both intracellularly and through secretion into the extracellular space. There are 22 known FGFs which act upon the four membrane bound FGFRs. Amongst the FGF ligands, 13 are known to be expressed in the CNS during embryonic development (Fgf1,2, 3,7,8, 9,10,13,15,16,17,18,22) in specific regions of the neuroepithelium (Figure 2). Three of the receptors, FGFR1, FGFR2 and FGFR3 are present in the embryonic brain. Indeed, FGFRs are among the earliest RTKs expressed in brain development.\nTwo FGF ligand molecules must bind a receptor dimer in order to cause receptor activation. FGF receptors, akin to other members of the RTK family of proteins, cross-phosphorylate their partner upon ligand binding, triggering the activation of three main intracellular pathways, the Ras/MAP Kinase, PI3 kinase, and PLCγ/Protein Kinase C (Schlessinger, 2000). The cascades eventually impinge upon the transcriptional machinery in the cell nucleus. Although RAS/MAPK and PI3K pathways are known to be important mediators of FGF signaling in the developing CNS, the relative role of each of these signaling pathways and of the other putative nuclear functions of FGF signaling for transcriptional regulation in stem/progenitor cells and biological functions are still unclear.\nConcurrently with patterning in the developing dorsal telencephalon, NSCs expand in number. Through a developmental switch not yet fully understood, after the majority of this expansion has occurred, stem cells then begin to generate neuronal precursors in a neurogenic phase that lasts for approximately 6 days in rodents and 10–12 weeks in primates (Caviness et al., 1995; Rakic, 1995) (Figure 1). Cortical excitatory neurons are derived from NSC that line the dorsal telencephalic ventricle. The primary stem cells in this ventricular zone (VZ) are called radial glia because of their expression of glial markers such as GFAP and GLAST, and their cellular morphology. Radial glial cells have an apical end foot attachment at the ventricle, a cell body that is near the ventricle, and a long radial process that is attached at the pial surface (Levitt et al., 1981). Radial glia can undergo self-renewing cell divisions, or asymmetric cell divisions that directly give rise to neurons (Noctor et al., 2001). Another product of radial glial division are committed neurogenic progenitors that migrate to the subventricular zone (SVZ), above the VZ, where they in turn proliferate to give rise to neurons. The committed neuronal progenitors of the SVZ, referred to as intermediate progenitor cells (IPCs) express the transcription factor TBR2 and lack the self-renewal properties of true stem cells (Pontious et al., 2008). However, their proliferation is important for the expansion of cortical layers, as demonstrated by the decrease in cortical surface area and thickness in mice lacking tbr2 (Arnold et al., 2008; Sessa et al., 2008).\nFibroblast growth factor signaling is important for the regulation of neurogenesis in the developing cortex. Studies in vitro originally suggested that the ability of a cortical NSC to stop self-renewing and begin the differentiation process was somehow delayed by increased FGF signaling, resulting in an expanded stem cell pool (Kilpatrick and Bartlett, 1993). The first in vivo demonstration was provided by injection of an FGF ligand, FGF2, in rat embryonic brain ventricles, which resulted in an expanded cortex with increased excitatory neuron production (Vaccarino et al., 1999). Conversely, the deletion of the fgf2 gene resulted in a cortex with reduced numbers of glutamatergic excitatory neurons, particularly in the anterior neocortex (Raballo et al., 2000; Korada et al., 2002). This was not due to a change in the cell cycle or by alterations in cell survival, suggesting that FGF signaling might affect the early amplification of stem cells or their immediate descendants (Raballo et al., 2000). This was confirmed by later work performed on FGF receptor knockout mice (see FGFs and the Developing Dorsal Telencephalon).\nSimilarly, mice with reduced fgf8 gene expression have decreased proliferation and increased numbers of apoptotic cells in the developing telencephalon (Fukuchi-Shimogori and Grove, 2001; Garel et al., 2003; Storm et al., 2006). However, reducing the gene dosages of fgf15 has opposite effects (Borello et al., 2008) with fgf15 expression in the telencephalon promoting cell differentiation, inhibiting proliferation, and promoting the expression of the coup-tf1 transcription factor, which plays a role in the development of layer four neurons and posterior cortex (Gimeno et al., 2003; Borello et al., 2008). Therefore, the combination of different FGFs and other cell extrinsic signaling proteins expressed in the neurogenic period may regulate the behavior of stem cells and the production of neuroblasts in a precise sequence, resulting in the establishment of a cortex with the correct number of neurons."}

{"project":"0_colil","denotations":[{"id":"20877431-11057895-637125","span":{"begin":958,"end":962},"obj":"11057895"},{"id":"20877431-7482802-637126","span":{"begin":1749,"end":1753},"obj":"7482802"},{"id":"20877431-7482803-637127","span":{"begin":1762,"end":1766},"obj":"7482803"},{"id":"20877431-7050307-637128","span":{"begin":2242,"end":2246},"obj":"7050307"},{"id":"20877431-11217860-637129","span":{"begin":2383,"end":2387},"obj":"11217860"},{"id":"20877431-18075251-637130","span":{"begin":2796,"end":2800},"obj":"18075251"},{"id":"20877431-18794345-637131","span":{"begin":2991,"end":2995},"obj":"18794345"},{"id":"20877431-18940588-637132","span":{"begin":3011,"end":3015},"obj":"18940588"},{"id":"20877431-8439411-637133","span":{"begin":3374,"end":3378},"obj":"8439411"},{"id":"20877431-10195217-637134","span":{"begin":3598,"end":3602},"obj":"10195217"},{"id":"20877431-10864959-637135","span":{"begin":3782,"end":3786},"obj":"10864959"},{"id":"20877431-11826116-637136","span":{"begin":3803,"end":3807},"obj":"11826116"},{"id":"20877431-10864959-637137","span":{"begin":4022,"end":4026},"obj":"10864959"},{"id":"20877431-11567107-637138","span":{"begin":4336,"end":4340},"obj":"11567107"},{"id":"20877431-12642494-637139","span":{"begin":4356,"end":4360},"obj":"12642494"},{"id":"20877431-16613831-637140","span":{"begin":4376,"end":4380},"obj":"16613831"},{"id":"20877431-18625063-637141","span":{"begin":4465,"end":4469},"obj":"18625063"},{"id":"20877431-12915315-637142","span":{"begin":4736,"end":4740},"obj":"12915315"},{"id":"20877431-18625063-637143","span":{"begin":4758,"end":4762},"obj":"18625063"}],"text":"FGF ligands, stem cell amplification and cortical neurogenesis\nFibroblast growth factor ligands are peptides that act both intracellularly and through secretion into the extracellular space. There are 22 known FGFs which act upon the four membrane bound FGFRs. Amongst the FGF ligands, 13 are known to be expressed in the CNS during embryonic development (Fgf1,2, 3,7,8, 9,10,13,15,16,17,18,22) in specific regions of the neuroepithelium (Figure 2). Three of the receptors, FGFR1, FGFR2 and FGFR3 are present in the embryonic brain. Indeed, FGFRs are among the earliest RTKs expressed in brain development.\nTwo FGF ligand molecules must bind a receptor dimer in order to cause receptor activation. FGF receptors, akin to other members of the RTK family of proteins, cross-phosphorylate their partner upon ligand binding, triggering the activation of three main intracellular pathways, the Ras/MAP Kinase, PI3 kinase, and PLCγ/Protein Kinase C (Schlessinger, 2000). The cascades eventually impinge upon the transcriptional machinery in the cell nucleus. Although RAS/MAPK and PI3K pathways are known to be important mediators of FGF signaling in the developing CNS, the relative role of each of these signaling pathways and of the other putative nuclear functions of FGF signaling for transcriptional regulation in stem/progenitor cells and biological functions are still unclear.\nConcurrently with patterning in the developing dorsal telencephalon, NSCs expand in number. Through a developmental switch not yet fully understood, after the majority of this expansion has occurred, stem cells then begin to generate neuronal precursors in a neurogenic phase that lasts for approximately 6 days in rodents and 10–12 weeks in primates (Caviness et al., 1995; Rakic, 1995) (Figure 1). Cortical excitatory neurons are derived from NSC that line the dorsal telencephalic ventricle. The primary stem cells in this ventricular zone (VZ) are called radial glia because of their expression of glial markers such as GFAP and GLAST, and their cellular morphology. Radial glial cells have an apical end foot attachment at the ventricle, a cell body that is near the ventricle, and a long radial process that is attached at the pial surface (Levitt et al., 1981). Radial glia can undergo self-renewing cell divisions, or asymmetric cell divisions that directly give rise to neurons (Noctor et al., 2001). Another product of radial glial division are committed neurogenic progenitors that migrate to the subventricular zone (SVZ), above the VZ, where they in turn proliferate to give rise to neurons. The committed neuronal progenitors of the SVZ, referred to as intermediate progenitor cells (IPCs) express the transcription factor TBR2 and lack the self-renewal properties of true stem cells (Pontious et al., 2008). However, their proliferation is important for the expansion of cortical layers, as demonstrated by the decrease in cortical surface area and thickness in mice lacking tbr2 (Arnold et al., 2008; Sessa et al., 2008).\nFibroblast growth factor signaling is important for the regulation of neurogenesis in the developing cortex. Studies in vitro originally suggested that the ability of a cortical NSC to stop self-renewing and begin the differentiation process was somehow delayed by increased FGF signaling, resulting in an expanded stem cell pool (Kilpatrick and Bartlett, 1993). The first in vivo demonstration was provided by injection of an FGF ligand, FGF2, in rat embryonic brain ventricles, which resulted in an expanded cortex with increased excitatory neuron production (Vaccarino et al., 1999). Conversely, the deletion of the fgf2 gene resulted in a cortex with reduced numbers of glutamatergic excitatory neurons, particularly in the anterior neocortex (Raballo et al., 2000; Korada et al., 2002). This was not due to a change in the cell cycle or by alterations in cell survival, suggesting that FGF signaling might affect the early amplification of stem cells or their immediate descendants (Raballo et al., 2000). This was confirmed by later work performed on FGF receptor knockout mice (see FGFs and the Developing Dorsal Telencephalon).\nSimilarly, mice with reduced fgf8 gene expression have decreased proliferation and increased numbers of apoptotic cells in the developing telencephalon (Fukuchi-Shimogori and Grove, 2001; Garel et al., 2003; Storm et al., 2006). However, reducing the gene dosages of fgf15 has opposite effects (Borello et al., 2008) with fgf15 expression in the telencephalon promoting cell differentiation, inhibiting proliferation, and promoting the expression of the coup-tf1 transcription factor, which plays a role in the development of layer four neurons and posterior cortex (Gimeno et al., 2003; Borello et al., 2008). Therefore, the combination of different FGFs and other cell extrinsic signaling proteins expressed in the neurogenic period may regulate the behavior of stem cells and the production of neuroblasts in a precise sequence, resulting in the establishment of a cortex with the correct number of neurons."}

{"project":"2_test","denotations":[{"id":"20877431-11057895-38520402","span":{"begin":958,"end":962},"obj":"11057895"},{"id":"20877431-7482802-38520403","span":{"begin":1749,"end":1753},"obj":"7482802"},{"id":"20877431-7482803-38520404","span":{"begin":1762,"end":1766},"obj":"7482803"},{"id":"20877431-7050307-38520405","span":{"begin":2242,"end":2246},"obj":"7050307"},{"id":"20877431-11217860-38520406","span":{"begin":2383,"end":2387},"obj":"11217860"},{"id":"20877431-18075251-38520407","span":{"begin":2796,"end":2800},"obj":"18075251"},{"id":"20877431-18794345-38520408","span":{"begin":2991,"end":2995},"obj":"18794345"},{"id":"20877431-18940588-38520409","span":{"begin":3011,"end":3015},"obj":"18940588"},{"id":"20877431-8439411-38520410","span":{"begin":3374,"end":3378},"obj":"8439411"},{"id":"20877431-10195217-38520411","span":{"begin":3598,"end":3602},"obj":"10195217"},{"id":"20877431-10864959-38520412","span":{"begin":3782,"end":3786},"obj":"10864959"},{"id":"20877431-11826116-38520413","span":{"begin":3803,"end":3807},"obj":"11826116"},{"id":"20877431-10864959-38520414","span":{"begin":4022,"end":4026},"obj":"10864959"},{"id":"20877431-11567107-38520415","span":{"begin":4336,"end":4340},"obj":"11567107"},{"id":"20877431-12642494-38520416","span":{"begin":4356,"end":4360},"obj":"12642494"},{"id":"20877431-16613831-38520417","span":{"begin":4376,"end":4380},"obj":"16613831"},{"id":"20877431-18625063-38520418","span":{"begin":4465,"end":4469},"obj":"18625063"},{"id":"20877431-12915315-38520419","span":{"begin":4736,"end":4740},"obj":"12915315"},{"id":"20877431-18625063-38520420","span":{"begin":4758,"end":4762},"obj":"18625063"}],"text":"FGF ligands, stem cell amplification and cortical neurogenesis\nFibroblast growth factor ligands are peptides that act both intracellularly and through secretion into the extracellular space. There are 22 known FGFs which act upon the four membrane bound FGFRs. Amongst the FGF ligands, 13 are known to be expressed in the CNS during embryonic development (Fgf1,2, 3,7,8, 9,10,13,15,16,17,18,22) in specific regions of the neuroepithelium (Figure 2). Three of the receptors, FGFR1, FGFR2 and FGFR3 are present in the embryonic brain. Indeed, FGFRs are among the earliest RTKs expressed in brain development.\nTwo FGF ligand molecules must bind a receptor dimer in order to cause receptor activation. FGF receptors, akin to other members of the RTK family of proteins, cross-phosphorylate their partner upon ligand binding, triggering the activation of three main intracellular pathways, the Ras/MAP Kinase, PI3 kinase, and PLCγ/Protein Kinase C (Schlessinger, 2000). The cascades eventually impinge upon the transcriptional machinery in the cell nucleus. Although RAS/MAPK and PI3K pathways are known to be important mediators of FGF signaling in the developing CNS, the relative role of each of these signaling pathways and of the other putative nuclear functions of FGF signaling for transcriptional regulation in stem/progenitor cells and biological functions are still unclear.\nConcurrently with patterning in the developing dorsal telencephalon, NSCs expand in number. Through a developmental switch not yet fully understood, after the majority of this expansion has occurred, stem cells then begin to generate neuronal precursors in a neurogenic phase that lasts for approximately 6 days in rodents and 10–12 weeks in primates (Caviness et al., 1995; Rakic, 1995) (Figure 1). Cortical excitatory neurons are derived from NSC that line the dorsal telencephalic ventricle. The primary stem cells in this ventricular zone (VZ) are called radial glia because of their expression of glial markers such as GFAP and GLAST, and their cellular morphology. Radial glial cells have an apical end foot attachment at the ventricle, a cell body that is near the ventricle, and a long radial process that is attached at the pial surface (Levitt et al., 1981). Radial glia can undergo self-renewing cell divisions, or asymmetric cell divisions that directly give rise to neurons (Noctor et al., 2001). Another product of radial glial division are committed neurogenic progenitors that migrate to the subventricular zone (SVZ), above the VZ, where they in turn proliferate to give rise to neurons. The committed neuronal progenitors of the SVZ, referred to as intermediate progenitor cells (IPCs) express the transcription factor TBR2 and lack the self-renewal properties of true stem cells (Pontious et al., 2008). However, their proliferation is important for the expansion of cortical layers, as demonstrated by the decrease in cortical surface area and thickness in mice lacking tbr2 (Arnold et al., 2008; Sessa et al., 2008).\nFibroblast growth factor signaling is important for the regulation of neurogenesis in the developing cortex. Studies in vitro originally suggested that the ability of a cortical NSC to stop self-renewing and begin the differentiation process was somehow delayed by increased FGF signaling, resulting in an expanded stem cell pool (Kilpatrick and Bartlett, 1993). The first in vivo demonstration was provided by injection of an FGF ligand, FGF2, in rat embryonic brain ventricles, which resulted in an expanded cortex with increased excitatory neuron production (Vaccarino et al., 1999). Conversely, the deletion of the fgf2 gene resulted in a cortex with reduced numbers of glutamatergic excitatory neurons, particularly in the anterior neocortex (Raballo et al., 2000; Korada et al., 2002). This was not due to a change in the cell cycle or by alterations in cell survival, suggesting that FGF signaling might affect the early amplification of stem cells or their immediate descendants (Raballo et al., 2000). This was confirmed by later work performed on FGF receptor knockout mice (see FGFs and the Developing Dorsal Telencephalon).\nSimilarly, mice with reduced fgf8 gene expression have decreased proliferation and increased numbers of apoptotic cells in the developing telencephalon (Fukuchi-Shimogori and Grove, 2001; Garel et al., 2003; Storm et al., 2006). However, reducing the gene dosages of fgf15 has opposite effects (Borello et al., 2008) with fgf15 expression in the telencephalon promoting cell differentiation, inhibiting proliferation, and promoting the expression of the coup-tf1 transcription factor, which plays a role in the development of layer four neurons and posterior cortex (Gimeno et al., 2003; Borello et al., 2008). Therefore, the combination of different FGFs and other cell extrinsic signaling proteins expressed in the neurogenic period may regulate the behavior of stem cells and the production of neuroblasts in a precise sequence, resulting in the establishment of a cortex with the correct number of neurons."}