Publications (20)79.79 Total impact
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Article: The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin.
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ABSTRACT: Spinal muscular atrophy (SMA), a frequent neurodegenerative disease, is caused by reduced levels of functional survival of motoneuron (SMN) protein. SMN is involved in multiple pathways, including RNA metabolism and splicing as well as motoneuron development and function. Here we provide evidence for a major contribution of the Rho-kinase (ROCK) pathway in SMA pathogenesis. Using an in vivo protein interaction system based on SUMOylation of proteins, we found that SMN is directly interacting with profilin2a. Profilin2a binds to a stretch of proline residues in SMN, which is heavily impaired by a novel SMN2 missense mutation (S230L) derived from a SMA patient. In different SMA models, we identified differential phosphorylation of the ROCK-downstream targets cofilin, myosin-light chain phosphatase and profilin2a. We suggest that hyper-phosphorylation of profilin2a is the molecular link between SMN and the ROCK pathway repressing neurite outgrowth in neuronal cells. Finally, we found a neuron-specific increase in the F-/G-actin ratio that further support the role of actin dynamics in SMA pathogenesis.Human Molecular Genetics 09/2011; 20(24):4865-78. · 7.64 Impact Factor -
Article: Polysialyltransferase overexpression in Schwann cells mediates different effects during peripheral nerve regeneration.
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ABSTRACT: The polysialic acid (PSA) moiety of the neural cell adhesion molecule (NCAM) has been shown to support dynamic changes underlying peripheral nerve regeneration. Using transgenic mice expressing polysialyltransferase ST8SiaIV under control of a glial-specific (proteolipid protein, PLP) promoter (PLP-ST8SiaIV-transgenic mice), we tested the hypothesis that permanent synthesis of PSA in Schwann cells impairs functional recovery of lesioned peripheral nerves. After sciatic nerve crush, histomorphometric analyses demonstrated impaired remyelination of regenerated axons at the lesion site and in target tissue of PLP-ST8SiaIV-transgenic mice, though the number and size of regenerating unmyelinated axons were not changed. This was accompanied by slower mechanosensory recovery in PLP-ST8SiaIV-transgenic mice. However, the proportion of successfully mono-(re)innervated motor endplates in the foot pad muscle was significantly increased in PLP-ST8SiaIV-transgenic mice when compared with wild-type littermates, suggesting that long-term increase in PSA levels in regenerating nerves may favor selective motor target reinnervation. The combined negative and positive effects of a continuous polysialyltransferase overexpression observed during peripheral nerve regeneration suggest that an optimized time- and differentiation-dependent control of polysialyltransferase expression in Schwann cells may further improve recovery after peripheral nerves injury.Glycobiology 08/2011; 22(1):107-15. · 3.58 Impact Factor -
Article: Erratum to: Characterization and differentiation potential of rat ventral mesencephalic neuronal progenitor cells immortalized with SV40 large T antigen.
Cell and Tissue Research 06/2010; · 3.11 Impact Factor -
Article: Characterization and differentiation potential of rat ventral mesencephalic neuronal progenitor cells immortalized with SV40 large T antigen.
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ABSTRACT: Neuronal progenitor cells (NPCs) possess high potential for use in regenerative medicine. To overcome their limited mitotic competence, various immortalization strategies have been applied that allow their prolonged maintenance and expansion in vitro. Such immortalized cells can be used for the design and discovery of new cell-based therapies for neurodegenerative diseases, such as Parkinson's disease. We immortalized rat ventral mesencephalic NPCs by using SV40 large T antigen (SV40Tag). All cell clones displayed a two- to three-fold higher proliferation rate compared with the primary cells. In order to induce dopaminergic differentiation of generated cell clones, both glial-derived neurotrophic factor and di-butyryl cyclic adenosine monophosphate were applied. Treated cells were then characterized regarding the expression of dopaminergic lineage markers, differentiation of various cell populations, calcium imaging in the presence of kainate, and immunohistochemistry after intrastriatal transplantation. Treated cells displayed morphological maturation, and calcium imaging revealed neuronal properties in the presence of kainate. These cells also expressed low mRNA levels of the dopamine transporter and tyrosine hydroxylase (TH), although no TH-immunopositive neurons were found. Intrastriatal transplantation into the neurotoxin-lesioned rats did not induce further differentiation. As an alternative approach, we silenced SV40Tag with short interfering RNA, but this was not sufficient to trigger differentiation into dopaminergic neurons. Nevertheless, neuronal and glial cells were detected as shown by beta-tubulin type III and glial fibrillary acidic protein staining, respectively. SV40Tag cells are suitable for carrying out controlled genetic modifications as shown by overexpression of enhanced green fluorescence protein after efficient non-viral transfection.Cell and Tissue Research 02/2010; 340(1):29-43. · 3.11 Impact Factor -
Article: Fibroblast growth factor-2 regulates the stability of nuclear bodies.
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ABSTRACT: Nuclear bodies are distinct subnuclear structures. The survival of motoneuron (SMN) gene is mutated or deleted in patients with the neurodegenerative disease spinal muscular atrophy (SMA). The gene product SMN is a marker protein for one class of nuclear bodies denoted as nuclear gems. SMN has also been found in Cajal bodies, which co-localize with gems in many cell types. Interestingly, SMA patients display a reduced number of gems. Little is known about the regulation of nuclear body formation and stabilization. We have previously shown that a nuclear isoform of the fibroblast growth factor-2 (FGF-2(23)) binds directly to SMN. In this study, we analyzed the consequences of FGF-2(23) binding to SMN with regard to nuclear body formation. On a molecular level, we showed that FGF-2(23) competed with Gemin2 (a component of the SMN complex that is necessary for gem stabilization) for binding to SMN. Down-regulation of Gemin2 by siRNA caused destabilization of SMN-positive nuclear bodies. This process is reflected in both cellular and in vivo systems by a negative regulatory function of FGF-2 in nuclear body formation: in HEK293 cells, FGF-2(23) decreased the number of SMN-positive nuclear bodies. The same effect could be observed in motoneurons of FGF-2 transgenic mice. This study demonstrates the functional role of a growth factor in the regulation of structural entities of the nucleus.Proceedings of the National Academy of Sciences 08/2009; 106(31):12747-52. · 9.68 Impact Factor -
Article: Mice lacking basic fibroblast growth factor showed faster sensory recovery.
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ABSTRACT: Neurotrophic factors have been shown to stimulate and support peripheral nerve repair. One of these factors is basic fibroblast growth factor (FGF-2), which is up-regulated after peripheral nerve injury and influences early sciatic nerve regeneration by regulating Schwann cell proliferation. Our previous study on FGF-2 deficient mice indicated that FGF-2 is important for axonal maturation and remyelination one week after sciatic nerve crush (Jungnickel, J., Claus, P., Gransalke, K., Timmer, M. and Grothe, C., 2004. Targeted disruption of the FGF-2 gene affects the response to peripheral nerve injury. Mol. Cell. Neurosci. 25, 444-452). However, the functional impact of these effects on sensory and motor fibers was not clear. After performing pinch test, walking track analysis and rotarod, we found faster recovery of mechanosensory but not of motor function in mutant mice. To elucidate the role of FGF-2 on structural recovery, we analyzed FGF-2 deficient mice and wild-type littermates 2 and 4 weeks after sciatic nerve crush. Two weeks after peripheral nerve injury, regenerating fibers of mutant mice showed both significantly increased axon and myelin size, but no difference in the number of myelinated and unmyelinated fibers. Molecular analysis indicated that the expression level of myelin protein zero was significantly enhanced in lesioned nerves in the absence of FGF-2. These results suggest that loss of FGF-2 could positively influence restoration of mechanosensory function by accelerating structural recovery transiently.Experimental Neurology 07/2009; 223(1):166-72. · 4.70 Impact Factor -
Article: Fibroblast growth factor 2 (FGF-2) is a novel substrate for arginine methylation by PRMT5.
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ABSTRACT: Fibroblast growth factor 2 (FGF-2) is expressed in isoforms of different molecular masses from one mRNA species by alternative start of translation. The higher molecular mass isoforms (FGF-2(21) and (23)) contain an arginine-rich N-terminus organized in RG-motifs followed by the 18 kDa FGF-2 (FGF-2(18)) core which is common to all isoforms. Both isoforms localize differentially to the nucleus. Here, we analyzed the nuclear localization of FGF-2(21). Surprisingly, the lack of one RG-motif in FGF-2(21) resulted in the nucleolar distribution characteristic of FGF-2(18). We have previously shown that 23 kDa FGF-2 (FGF-2(23)) interacts specifically with the survival of motoneuron (SMN) protein, an assembly protein for small nuclear ribonucleoprotein particles. For this assembly, Sm-proteins methylated by protein arginine methyltransferase 5 (PRMT5) are required. In our study, we aimed to analyze whether FGF-2(23) is also a substrate for symmetrical methylation by PRMT5. We could confirm that both proteins exist in a common complex. Moreover, PRMT5 methylates FGF-2(23) in vitro, whereas mutated inactive PRMT5 does not. FGF-2(23) is therefore a new substrate of PRMT5. With regard to function, inhibition of methyltransferase activity in HEK293T cells leads to cytoplasmic enrichment of FGF-2, indicating the importance of arginine methylation for shuttling of FGF-2(23) to the nucleus.Biological Chemistry 02/2009; 390(1):59-65. · 2.96 Impact Factor -
Article: Up-regulation of platelet-derived growth factor by peripheral-blood leukocytes during experimental allergic encephalomyelitis.
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ABSTRACT: In multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), clinical disease is associated with infiltration of the central nervous system (CNS) by immune cells. Subsequent remission with remyelination has been linked to an increased occurrence of oligodendrocyte progenitor (O2A) cells. Platelet-derived growth factor (PDGF) and fibroblast growth factor-2 (FGF-2) are key growth factors for O2A cells, yet little is known about their relevance in EAE and MS. We analyzed the expression of PDGF, FGF-2, and their receptors by peripheral-blood leukocytes (PBLs) and lymphocyte subsets during MBP-induced EAE. Strong up-regulation of PDGF, but not FGF-2, was observed in PBLs, with the highest expression after the disease maximum. T, NK, and NKT cells expressed PDGF, which is a novel observation because thus far only monocytes/macrophages have been reported to express PDGF. These results extend the idea that growth factors may contribute to improved CNS tissue repair, including PDGF, which is secreted by lesion-homing immune cells. The production of PDGF by lymphocytes may have potential therapeutic value when activating or modulating T-cell responses in demyelinating diseases.Journal of Neuroscience Research 03/2008; 86(2):392-402. · 2.74 Impact Factor -
Article: Expression and regulation of Sef, a novel signaling inhibitor of receptor tyrosine kinases-mediated signaling in the nervous system.
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ABSTRACT: Fibroblast growth factors (FGFs) signal via four distinct high affinity cell surface tyrosine kinase receptors, termed FGFR1-FGFR4 (FGFR-FGF-receptor). Recently, a new modulator of the FGF signaling pathway, the transmembrane protein 'similar expression to FGF genes' (Sef), has been identified in zebrafish and subsequently in mammals. Sef from mouse and human inhibits FGF mitogenic activity. In the present study, we analyzed the expression of Sef in distinct rat brain areas, in the spinal cord and in peripheral nerves and spinal ganglia using semi-quantitative RT-PCR. Furthermore, we studied the cellular expression pattern of Sef in intact spinal ganglia and sciatic nerves and, in addition, after crush lesion, using in situ hybridization and immunohistochemistry. Sef transcripts were expressed in all brain areas evaluated and in the spinal cord. A neuronal expression was found in both intact and injured spinal ganglia. Intact sciatic nerves, however, showed little or no Sef expression. Seven days after injury, high Sef expression was concentrated to the crush site, and Schwann cells seemed to be the source of Sef. The labeling pattern of up-regulated Sef was complementary to the patterns of FGF-2 and FGFR1-3, which were localized proximal and distal to the crush site. These results suggest an involvement of Sef during the nerve regeneration process, possibly by fine-tuning the effects of FGF signaling.Acta Histochemica 02/2008; 110(2):155-62. · 1.83 Impact Factor -
Article: Chromatin compaction and cell death by high molecular weight FGF-2 depend on its nuclear localization, intracrine ERK activation, and engagement of mitochondria.
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ABSTRACT: Fibroblast growth factor 2 (FGF-2) is produced as CUG-initiated, 22-34 kDa or AUG-initiated 18 kDa isoforms (hi- and lo-FGF-2, respectively), with potentially distinct functions. We report that expression of hi-FGF-2 in HEK293 cells elicited chromatin compaction preceding cell death with apoptotic features. Nuclear localization of the intact protein was required as expression of a non-nuclear hi-FGF-2 mutant failed to elicit chromatin compaction. Equally ineffective, despite nuclear localization, was the over-expression of the 18 kDa core sequence (lo-FGF-2). Chromatin compaction by hi-FGF-2 was accompanied by increased cytosolic cytochrome C, and was attenuated either by over-expression of Bcl-2 or by a peptide inhibitor of the pro-apoptotic protein Bax. In addition hi-FGF-2 elicited sustained activation of total and nuclear extracellular signal regulated kinase (ERK1/2) by an intracrine route, as it was not prevented by neutralizing anti-FGF-2 antibodies. Inhibition of the ERK1/2 activating pathway by dominant negative upstream activating kinase, or by PD 98059, prevented chromatin compaction by hi-FGF-2. ERK1/2 activation was not affected by the Bax-inhibiting peptide suggesting that it occurred upstream of mitochondrial involvement. We conclude that the hi-FGF-2-induced chromatin compaction and cell death requires its nuclear localization, intracrine ERK1/2 activation and mitochondrial engagement.Journal of Cellular Physiology 01/2008; 213(3):690-8. · 3.87 Impact Factor -
Article: The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus.
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ABSTRACT: Spinal muscular atrophy is a neurodegenerative disease accompanied by a loss of motoneurons. Either mutations or deletions in the survival of motoneuron (SMN) gene are responsible for this defect. SMN is an assembly protein for RNA-protein complexes in the nucleus and is also found in axons of neurons. However, it is unclear which dysfunctions of SMN are important for disease progression. In this study we analyzed the contributions of different SMN regions for localization and neuronal differentiation associated with outgrowth of neurites. Suppression of endogenous SMN protein levels significantly decreased the growth of neurites. Down-regulation of the interacting protein gemin2 had the opposite effect. Surprisingly, selective overexpression of the SMN C-terminal domain promoted neurite outgrowth similar to full-length protein and could rescue the SMN knock-down effects. The knock-down led to a significant change in the G-/F-actin ratio, indicating a role for SMN in actin dynamics. Therefore, our data suggest a functional role for SMN in microfilament metabolism in axons of motoneurons.The FASEB Journal 06/2007; 21(7):1492-502. · 5.71 Impact Factor -
Article: In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.
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ABSTRACT: Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood-brain barrier, oral administration may allow deceleration of progressive alpha-motoneurone degeneration by epigenetic SMN2 gene activation.Journal of Neurochemistry 08/2006; 98(1):193-202. · 4.06 Impact Factor -
Article: Valproic acid promotes neurite outgrowth in PC12 cells independent from regulation of the survival of motoneuron protein.
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ABSTRACT: Spinal muscular atrophy (SMA) is a neurodegenerative disorder of motoneurons. The disease is caused by deletions or mutations of the survival of motoneuron gene 1 (SMN1). The amount of protein expressed from the second gene, SMN2, correlated with the severity of the clinical phenotype. The histone deacetylase inhibitor valproic acid (VPA) has been shown to increase the total cellular amount of functional SMN protein and is therefore considered as a drug candidate for treatment of SMA. In this study, we analyzed the effects of VPA in PC12 cells, a model system for neuronal differentiation, with regard to neurite outgrowth and SMN expression. VPA promoted neurite outgrowth in PC12 cells. However, this effect did not correlate with upregulation of SMN protein levels, suggesting a SMN-independent mechanism for VPA regulation of neurite outgrowth.Chemical Biology & Drug Design 04/2006; 67(3):244-7. · 2.28 Impact Factor -
Article: Rat embryonic motoneurons in long-term co-culture with Schwann cells--a system to investigate motoneuron diseases on a cellular level in vitro.
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ABSTRACT: Investigations of motoneuron diseases on a cellular and molecular level require long-term cultivation of primary cells. Here we present a new culture system in which matured motoneurons interact with their physiological partners like interneurons, astroglia and peripheral glia cells. This enables motoneuron-maturation for up to 3 weeks, while motoneurons consistently reached large diameters of their somata of 30-45 microm, occasionally more than 80 microm. Dissociated rat embryonic ventral spinal cord cells were enriched for motoneurons by density gradient centrifugation and seeded on a non-confluent mono-layer of highly enriched neonatal rat Schwann cells. Immunocytochemical visualization of neuron specific betaIII-tubulin in all neurons and of motoneuron specific non-phosphorylated neurofilament H/M, respectively, revealed that after 3 days in vitro >70% of all neurons were motoneurons. After 20 days in vitro, a motoneuron fraction of 12% was maintained. Motoneurons were susceptible to transient transfection with green fluorescent protein cDNA when liposomal transfection and an enhancer substance were combined. Synaptic connections enabled formation of spontaneously active neuronal networks which provide a culture model to study glutamate excitotoxicity and calcium deregulation on a molecular level. Both mechanisms are implied in the pathophysiology of amyotrophic lateral sclerosis, a neurodegenerative motoneuron disorder.Journal of neuroscience methods 03/2005; 142(2):275-84. · 2.30 Impact Factor -
Article: Fibroblast growth factor-2(23) binds directly to the survival of motoneuron protein and is associated with small nuclear RNAs.
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ABSTRACT: The SMN (survival of motoneuron) protein is mutated in patients with the neurodegenerative disease spinal muscular atrophy. We have shown previously that a high-molecular-mass isoform of FGF (fibroblast growth factor) 2 (FGF-2(23)) is in a complex with SMN [Claus, Doring, Gringel, Muller-Ostermeyer, Fuhlrott, Kraft and Grothe (2003) J. Biol. Chem. 278, 479-485]. FGF-2 is a neurotrophic factor for motoneurons, and is known not only as a classical extracellular growth factor, but also as a nuclear protein. In the present study, we demonstrate that SMN binds to the arginine-rich N-terminus of FGF-2(23). In turn, FGF-2(23) interacts with amino acid residues 1-90 of the human SMN protein. This sequence displays nucleic-acid-binding capacity and overlaps partially with known binding sites for Gemin2/SIP1 (SMN-interacting protein 1) and p53. Finally, as a functional consequence of FGF-2(23) binding to SMN, FGF-2(23) is in a complex with the small nuclear RNAs U2 and U4. Since SMN functions as an assembly factor for snRNPs (small nuclear ribonucleoprotein particles), these results suggest binding of FGF-2(23) to snRNPs.Biochemical Journal 01/2005; 384(Pt 3):559-65. · 4.90 Impact Factor -
Article: Nuclear fibroblast growth factor-2 interacts specifically with splicing factor SF3a66.
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ABSTRACT: Fibroblast growth factor 2 (FGF-2) has a dual role as a classical extracellular signaling protein and as an intracellular factor. Isoforms of FGF-2, resulting from alternatively used start codons on one mRNA species, locate differentially to nuclear compartments. In this study we aimed to analyze functions of intracellular FGF-2 by identification of interacting proteins. We identified the 66-kDa subunit of splicing factor 3a (SF3a66) as a binding partner in a yeast two-hybrid screen and confirmed this interaction by pull-down assays. The splicing factor interacted with the 18-kDa (FGF-2(18)) and with the 23-kDa (FGF-2(23)) isoforms, indicating an interaction with a domain common to both isoforms. Moreover, FGF-2 interacted with the C-terminus of SF3a66, a sequence that has not previously been assigned a functional role. In a functional neurite outgrowth assay, SF3a66 enhanced neurite lengths similar to FGF-2(18). We have previously identified the spliceosomal assembly factor survival of motoneuron (SMN) protein as a protein interacting specifically with the FGF-2(23) isoform [Claus et al., J. Biol. Chem. 278 (2003), 479-485]. The identification of two FGF-2 interacting proteins from the same biochemical pathway suggests a novel intranuclear role of FGF-2.Biological Chemistry 01/2005; 385(12):1203-8. · 2.96 Impact Factor -
Article: Expression of the fibroblast growth factor-2 isoforms and the FGF receptor 1-4 transcripts in the rat model system of Parkinson's disease.
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ABSTRACT: Basic fibroblast growth factor (FGF)-2 occurs in different isoforms representing different translation products of a single mRNA. We have previously shown that the high molecular weight FGF-2 isoforms (21, 23 kD) stimulated survival- and neurite-promoting activities and protective effects on cultured embryonic dopaminergic (DA) neurons of the substantia nigra (Neuroscience 100 (2000) 73). In this study the expression of FGF-2 isoforms in the striatum and substantia nigra was analyzed by Western blot in adult intact rats and following complete unilateral 6-hydroxydopamine (6-OHDA) lesion. In intact rats, all three FGF-2 isoforms (18, 21, 23 kD) are expressed. Neurotoxin-mediated lesion of nigral DA neurons revealed no change of the FGF-2 isoform expression pattern in the nigrostriatal system. Additionally, the FGF receptors 1, 2 and 3 are expressed in these tissues and displayed no alterations after 6-OHDA injection as demonstrated by RT-PCR. The presence of all three FGF-2 isoforms and the FGFR 1-3, together with the previous demonstrated neurotrophic effects of FGF-2 on dopaminergic neurons, suggest a physiological function of the FGF-2 isoforms in the nigrostriatal system.Neuroscience Letters 05/2004; 360(3):117-20. · 2.11 Impact Factor -
Article: Targeted disruption of the FGF-2 gene affects the response to peripheral nerve injury.
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ABSTRACT: Basic fibroblast growth factor (FGF-2) is involved in the development, maintenance, and survival of the nervous system. To study the physiological role of endogenous FGF-2 during peripheral nerve regeneration, we analyzed sciatic nerves of FGF-2-deleted mice by using morphometric, morphological, and immunocytochemical methods. Quantification of number and size of myelinated axons in intact sciatic nerves revealed no difference between wild-type and FGF-2 knock-out (ko) animals. One week after nerve crush, FGF-2 ko mice showed about five times more regenerated myelinated axons with increased myelin and axon diameter in comparison to wild-types close to the injury site. In addition, quantitative distribution of macrophages and collapsed myelin profiles suggested faster Wallerian degeneration in FGF-2-deleted mice close to the lesion site. Our results suggest that endogenous FGF-2 is crucially involved in the early phase of peripheral nerve regeneration possibly by regulation of Schwann cell differentiation.Molecular and Cellular Neuroscience 04/2004; 25(3):444-52. · 3.66 Impact Factor -
Article: Differential intranuclear localization of fibroblast growth factor-2 isoforms and specific interaction with the survival of motoneuron protein.
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ABSTRACT: Fibroblast growth factor 2 (FGF-2) is an important modulator of cell growth and differentiation and a neurotrophic factor. FGF-2 occurs in isoforms, at a low molecular weight of 18,000 and at least two high molecular weight forms (21,000 and 23,000), representing alternative translation products from a single mRNA. In addition to its role as an extracellular ligand, FGF-2 localizes to the nuclei of cells. Here we show differential localization of the 18- and 23-kDa isoforms in the nuclei of rat Schwann cells. Whereas the 18-kDa isoform was found in the nucleoli, nucleoplasm, and Cajal bodies, the 23-kDa isoform localized in a punctuate pattern and associates with mitotic chromosomes suggesting different functional roles of the isoforms. Moreover, we show here that the 23-kDa FGF-2 isoform co-immunoprecipitates specifically with the survival of motor neuron protein (SMN). SMN is an assembly and recycling factor of the splicing machinery and locates to the cytoplasm, the nucleoplasm, and nuclear gems, where it co-localizes with 23-kDa FGF-2. Patients with spinal muscular atrophy suffer from fatal degeneration of motoneurons because of mutations and deletions of the gene for the SMN protein.Journal of Biological Chemistry 02/2003; 278(1):479-85. · 4.77 Impact Factor -
Article: In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia
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ABSTRACT: Basic fibroblast growth factor (FGF-2) is involved in several cellular processes of the nervous system during development, maintenance, and regeneration. In the central nervous system, FGF-2 has been shown to be expressed in neurons and glial cells, depending on the developmental stage and brain area. In the present study, a comprehensive analysis was performed of the cellular distribution of the transcripts of FGF-2 and of the FGF high-affinity receptors (R) 1–4 in intact and lesioned sciatic nerve and spinal ganglia. In the adult rat sciatic nerve FGF-2, FGFR1–3 were expressed at low levels as revealed by reverse transcriptase-polymerase chain reaction (RT-PCR). Sciatic nerve crush resulted in an increase of these transcript levels. FGFR4 expression was not detected in the intact and crushed nerve as revealed by RT-PCR and RNase protection assay. In situ hybridization using riboprobes for FGF-2, FGFR1–3 displayed staining in diverse cell types. Immunocytochemical staining of consecutive sections with cell markers for myelin, macrophages, and neurons revealed colocalization of the transcripts with Schwann cells and macrophages. In addition to FGF-2 and FGFR1, the transcripts of FGFR2–4 were expressed in neurons of spinal ganglia. Crush lesion of the sciatic nerve resulted in no alterations of the FGFR1–4 transcripts, whereas FGF-2 and FGFR3 mRNAs were up-regulated in spinal ganglia. The expression of FGFRs and FGF-2 in Schwann cells and macrophages at the lesion site of the sciatic nerve and in sensory neurons suggests that FGF-2 is involved in specific functions of these cells during regeneration. J. Comp. Neurol. 434:342–357, 2001. © 2001 Wiley-Liss, Inc.The Journal of Comparative Neurology 06/2001; 434(3):342 - 357. · 3.81 Impact Factor
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2001–2011
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Medizinische Hochschule Hannover
- • Institute of Neuroanatomy
- • Centre for Anatomy
Hannover, Lower Saxony, Germany
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