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1 The 21st Century COE program ‘Cell Fate Regulation Research and Education Unit’
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Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
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Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara 228-8555, Japan
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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Introduction |
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Glycosphingolipids (GSLs) are molecules ubiquitously expressed in the plasma membrane of cells (Hakomori 1990). Expression of GSLs is abundant in neural cells and drastically changed during development of central nervous system (Yu 1994). Recently, GSLs were revealed to form GSL-enriched microdomains, lipid rafts (also known as detergent-resistant membrane or detergent-insoluble membrane) at the cell surface membrane by being clustered with sphingomyelin and/or cholesterol (Hakomori et al. 1998; Simons & Toomre 2000). Lipid rafts have been suggested to be important for modulation of signal transduction and cell adhesion. Therefore, it is expected that lipid rafts are involved in organization of nervous systems via regulation of cytokine signalling and cell adhesion in neural precursor cells. However, formation and functions of lipid rafts in neural precursor cells are unclear.
In this study, we tried to clarify functions of lipid rafts in embryonic neural precursor cells. In mouse embryonic neuroepithelial cells treated with an inhibitor for lipid rafts, methyl-ß-cyclodextrin (MBCD, Scheiffele et al. 1997), integrin-fibronectin interaction-dependent adhesion was inhibited. Treatment of NECs with MBCD abolished LIF-induced activation of ERK but not STAT3. This study is the first report that characterized functions of lipid rafts in embryonic neural precursor cells.
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Results |
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NECs abundantly contain immature neural precursor cells capable of differentiating to mature astrocytes and neurones in vitro (Bonni et al. 1997; Nakashima et al. 1999b, 2001; Sun et al. 2001). In these reports, propagation of NECs in culture was possible by culturing the cells on dishes that had been coated with poly L-ornithine and fibronectin. Since cell adhesion to fibronectin-containing substratum is known to be mediated by fibronectin receptor, we wanted to confirm whether NEC adhesion to the culture dish is mediated by integrin-fibronectin interaction. For this purpose, NECs, just before plating on to fibronectin-coated dish, were treated with Arg-Gly-Asp (RGD) peptide, which is present in fibronectin and is recognized by fibronectin receptor such as 
5ß1 integrin (Pierschbacher & Ruoslahti 1984). As shown in Fig. 1A,B, adhesion of RGD peptide-treated NECs was significantly inhibited, suggesting that adhesion of NECs in this experimental system is dependent on the interaction between integrin molecules in the cells and fibronectin substratum.
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Among fibronectin-binding integrin molecules, 5ß1 integrin recognizes Arg-Gly-Asp sequence, while 4ß1 does other sequence, Glu-Ile-Leu-Asp-Val (Garcia-Pardo et al. 1990). Thus, it is considered that Arg-Gly-Asp sequence-recognized integrins are involved in NEC adhesion. In NECs, such as 5, v and ß1 subunit of the integrin molecules were expressed (Fig. 1C). Since 5ß1 and vß1 integrin molecules recognize Arg-Gly-Asp sequence and interact with fibronectin (Hynes 1992), it was suggested that NEC adhesion is mediated by integrin molecules such as 5ß1 and vß1. To reveal the intracellular distribution of fibronectin-binding integrin molecules in NECs, distribution of ß1 subunit, a common component of these integrin molecules, in lipid rafts was examined. To prepare lipid rafts, NEC homogenate was subjected to sucrose gradient ultracentrifuge, and the gradient samples were fractionated into 10 fractions. As shown in Fig. 1D, almost 90% of the total proteins were distributed in high density fraction (fractions 9 and 10). Flotillin-1, a marker protein of lipid rafts (Bickel et al. 1997), was detected in fraction 4 (Fig. 1E). ß1 integrin was also selectively detected in fraction 4, indicates the localization of fibronectin-binding integrin molecules in lipid rafts as previously reported by Tai et al. (2003).
NEC adhesion is dependent on lipid rafts
Next, to clarify whether lipid rafts are involved in integrin-fibronectin interaction-dependent NEC adhesion, NECs were treated with MBCD, an inhibitory molecule that binds to cholesterol and disrupts functions of lipid rafts (Scheiffele et al. 1997). In NECs treated with MBCD, distribution of Flotillin-1 in lipid raft fraction (fraction 4) was decreased (Fig. 1F), suggesting that MBCD actually disrupted lipid rafts in NECs. Most of NECs treated with MBCD were detached from fibronectin substratum by MBCD treatment (Fig. 1G,H), although MBCD did not severely affect the viability of NECs (None, 93.0% ± 1.5; MBCD, 85.6% ± 2.0). These results suggest that NEC adhesion mediated by integrin molecules is dependent on lipid rafts.
GSLs are not required for NEC adhesion
Lipid rafts are formed by GSLs, sphingomyelin and cholesterol at cell surface (Hakomori et al. 1998; Simons & Toomre 2000). NECs abundantly expressed sialic acid-containing GSLs, gangliosides (Fig. 2A). These gangliosides, GD3, GT1b and GQ1b, belong to b-series ganglioside. The expression of GD3 was the most predominant (GD3, 65.4%; GT1b, 23.1%; GQ1b, 11.5%. sialic acid distribution). As compared with acidic GSLs, expression of neutral GSL was very weak (data not shown). Furthermore, galactose-based GSLs, such as GalCer and sulphatide, were detected in NEC-derived oligodendrocytes, but not in NECs (Fig. 2B,C). To analyse the function of GSLs in NEC adhesion, NECs were treated with D-threo-1-phenyl-2-decanoylamin-3-morpholino-propanol (PDMP), an inhibitor for glucosylceramide synthase (Inokuchi & Radin 1987). Since expression of galactose-based GSLs such as GalCer and sulphatide was not detected in NECs, PDMP treatment is considered to induce GSL depletion in NECs. In fact, expression of GD3, a major GSL in NECs, was depleted in PDMP-treated NECs (Fig. 2D). However, NEC adhesion to fibronectin substratum (Fig. 2E,F) was not affected in these cells. Ostermeyer et al. (1999) reported that GSLs are not essential for the formation of lipid rafts in NECs. In fact, PDMP did not affect the localization of flotillin-1 in lipid rafts of NECs (Fig. 2G). Therefore, these results suggest that GSLs, components of lipid rafts, are not necessarily required for NEC adhesion mediated by integrin-fibronectin interaction. In contrast, when excess exogenous GD3 (10 or 40 µM) were incorporated in intact NECs, the adhesion was inhibited (Fig. 2H). It is consider to attribute to perturbation of lipid raft stability (Simons & Toomre 2000).
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IL-6 type cytokines (IL-6, IL-11, LIF, ciliary neurotrophic factor, oncostatin M, cardiotrophin 1 and cardiotrophin-like cytokine) induce astrocyte differentiation of NECs in cooperation with BMPs (Nakashima et al. 1999b; Yanagisawa et al. 2001). IL-6 type cytokines mainly activate two distinct signalling pathways, the JAK-STAT pathway and the Ras-MAPK pathway, via homo- or heterodimerization of the common signal transducer, gp130 (Taga & Kishimoto 1997). Some of the molecules mediating signalling of IL-6 type cytokines, for instance gp130, STAT3, Ras, SOS and ERK2, were reported to be distributed in lipid rafts (Wu et al. 1997; Mitani et al. 2001; Sehgal et al. 2002). We examined whether these molecules are distributed in lipid rafts of NECs. In NECs, gp130, JAK and Ras were detected in the lipid raft fraction (fraction 4) and the high density fraction (fractions 9–10) (Fig. 3, left panels). However, STAT3, SHP2 and ERK2 were not significantly distributed in the lipid raft fraction of NECs. This distribution pattern of gp130 signalling molecules and flotillin-1 in NECs was not changed after stimulation with LIF (Fig. 3, right panels).
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Next, we tried to examine whether lipid rafts in NECs are involved in gp130 signalling induced by LIF. NECs were treated with MBCD (Fig. 4A) and then stimulated with LIF. In MBCD-treated NECs, activation of STAT3 was not affected at all (Fig. 4B). In contrast, activation of ERK1 and ERK2 was repressed in MBCD-treated NECs, suggesting that the Ras-MAPK pathway is dependent on lipid rafts. Since combined stimulation by both the cytokines and extracellular matrices is reported to be required for either strong or sustained ERK activation (Assoian & Schwartz 2001), the ERK repression by MBCD might be due to the indirect effect via inhibition of the integrin signalling (Fig. 1). It is well known that activated STAT3 molecules dimerize and are translocate from cytoplasm to nucleus, where they bind to target gene promoters harbouring STAT3 binding element (TTNCNNAA where N represents any nucleotide) (Taga & Kishimoto 1997). To confirm whether LIF-induced activation of STAT3 is independent on lipid rafts, DNA binding activity of STAT3 in MBCD-treated NECs was analysed by DNA affinity precipitation using biotin-conjugated STAT binding element (SBE-oligo). As shown in Fig. 4C, DNA binding activity of STAT3 was also detected in NECs that had been treated with MBCD. Furthermore, up-regulation of glial fibrillary acidic protein (GFAP) and (suppressor of cytokine signalling 3) SOCS3, target genes of activated STAT3, was induced by LIF in NECs regardless of treatment with MBCD (Fig. 4D). Thus, these results indicate that LIF-induced activation of the JAK-STAT pathway in NECs does not require lipid rafts, nevertheless JAK1is distributed in lipid rafts. Also in PDMP-treated NECs, LIF-induced STAT3 activation was not affected (manuscript in preparation).
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Discussion |
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5ß1 integrin to fibronectin. However, in NECs with GSL-depletion by PDMP-treatment, adhesion to fibronectin substratum was not affected. Furthermore, adhesion to fibronectin substratum was inhibited in NECs that incorporated exogenous GD3 ganglioside. Thus, it is suggested that adhesion to fibronectin substratum in NECs does not require GSLs and is inhibited by excess GSLs probably via perturbation of lipid rafts. ß1 integrin regulates migration with 6 integrin and proliferation with v or 5 integrin in neural precursor cells (Jacques et al. 1998). Fibronectin, a ligand for some integrin molecules, is expressed in the developing brain (Stewart & Pearlman 1987). Lipid rafts may mediate the localization and proliferation of neural precursor cells via ß1 integrin in the physiological condition. IL-6 type cytokines represent a wide range of activities on various cell types, for instance those in the hemetopoietic and nervous systems, via activation of signalling pathways, JAK-STAT pathway, Ras-MAPK pathway and PI3 kinase-Akt pathway (Taga & Kishimoto 1997). These signalling pathways are triggered by homo- or heterodimerization of gp130, the common signal transducer of IL-6 type cytokines, which is reported to be distributed in lipid rafts (Mitani et al. 2001). In this study, we show that among JAK1, Ras and STAT3 which function downstream of gp130, the former two but not the latter were distributed in lipid rafts also in NECs as reported by Sehgal et al. (2002), in which all three were found in lipid rafts of hepatocarcinoma cells. Thus, it is proposed that distribution of these molecules in cell surface microdomains may differ from cell type to cell type. Interestingly, LIF-induced activation of STAT3 and up-regulation of its target gene expression were not affected in MBCD-treated NECs, indicating that activation of the JAK-STAT3 pathway is independent on lipid rafts at least in this particular cell type. Activation of the JAK-STAT pathway in hepatocarcinoma cells was inhibited by MBCD-treatment (Sehgal et al. 2002), suggesting that dependency of STAT3 activation may have some relationship to its distribution in lipid rafts. In developing brain, gp130 signalling induces astrocyte differentiation via activation of STAT3 (Nakashima et al. 1999a; Yanagisawa et al. 2000). In MBCD-treated NECs, it was easily expected that STAT3-mediated astrocyte differentiation normally occur. However, since MBCD-treated NECs underwent detachment from the culture dish substratum, we could not continue to culture MBCD-treated NECs and examine the involvement of lipid rafts in LIF-induced cell fate regulation.
It is suggested that lipid rafts are involved in cell adhesion and cytokine responsiveness regulating the fate of neural precursor cells (for example, EGF, erythropoietin and BMPs). In this study, we found that lipid rafts in NECs contribute to integrin-fibronectin interaction-dependent adhesion and activation of Ras-MAPK pathway, but not in activation of JAK-STAT pathway induced by LIF. More detailed studies focused on lipid rafts will be necessary for complete understanding of their role in neural precursor cells and neural development.
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Experimental procedures |
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NECs were prepared from telencephalons of ICR mouse embryo (E14.5) as previously described (Nakashima et al. 1999a). Mice were treated according to the guidelines of the Kumamoto University Centre for Animal Resources and Development. NECs were cultured in N2-supplemented DMEM/F12 medium containing 10 ng/mL of human recombinant bFGF (R&D Systems) on dishes that had been precoated with poly L-ornithine (Sigma) and fibronectin (Nitta Gelatin Inc). To examine the involvement of integrin molecules such as 5ß1 integrin in NEC adhesion, the cells were detached and treated with RGD peptide (0.5 or 1 µM, BIOMOL) for 30 min at 37 °C, and then replated on to precoated 96-well plates. Thirty minutes later, floating cells were removed by changing medium and then the number of attached cells was measured. To inhibit functions of lipid rafts or GlcCer synthesis, NECs were treated with MBCD (10 mM for 1 h at 37 °C, Sigma) or PDMP (10 µM for 5 days at 37 °C, Calbiochem), respectively. The viability of NECs was evaluated by a Vi-cell, cell viability analyser (Beckman Coulter). Immunocytochemical staining was performed using anti-GD3 antibody (Seikagaku Corporation), Biotin-conjugated anti-mouse IgM antibody (Jackson ImmunoResearch) and FITC-conjugated streptavidin (Vector Laboratories). Hoechst33258 (Nacalai tesque) was used to stain nuclei. GD3 incorporation was performed by culturing NECs in serum-free DMEM containing GD3 (Matreya) for 6 h at 37 °C.
RT-PCR
RT-PCR was performed as previously described (Yanagisawa et al. 2000). Used primer sets were as follows: 5'-TCC ACA GAA AAC TTC ACC CGG-3', 5'-AAG TAG CTG TCA TCA TAG ACG G-3' (for 5 integrin); 5'-TGG CCA GGG ATT TTG TCA AGG-3', 5'-CTC CTG AGA CAA AAT CTT CAA TG-3' (for v integrin); 5'-ATT GGC TTT GGC TCA TTT GTG G-3', 5'-CCA GCA GTC GTG TTA CAT TCC-3' (for ß1 integrin); 5'-CAC ATG AAG CCA CCC TGG CTC-3', 5'-GTA GAT CCT GGT ACT CCT GCA G-3' (for GFAP); 5'-GCT TCG ACT GTG TAC TCA AGC-3', 5'-AGC ATC ATA CTG ATC CAG GAA C-3' (for SOCS3); 5'-ACC ACA GTC CAT GCC ATC AC-3', 5'-TCC ACC ACC CTG TTG CTG TA-3' (for glyceraldehyde-3-phosphate dehydrogenase, G3PDH).
Preparation of lipid rafts
Preparation of lipid raft was performed according to the method by Iwabuchi et al. (1998) using hypertonic Na2CO3 solution or lysis buffer containing TritonX-100. In the former condition, NECs were homogenized in 1 mL of 0.5 M Na2CO3 using a loose fitting homogenizer (20 strokes) and a bath sonicator (three 30-s bursts). NEC homogenate was placed at the bottom of ultracentrifuge tube and mixed with an equal volume of 90% sucrose (w/v) in 25 mM MES, pH 6.5, 0.15 M NaCl (MES-buffered saline, MBS). The homogenate was then overlaid with 6 mL of 35% sucrose and 4 mL of 5% sucrose in MBS containing 250 mM sodium carbonate, and centrifuged at 175 000 g for 18 h in a Beckman SW41 rotor. In the latter condition, NEC homogenates were prepared with lysis buffer containing 1% Triton X-100, 10 mM Tris-HCl (pH 7.4), 150 mM NaCl, 5 mM EDTA, 5 µg/mL aprotinin, 2 mM Na3VO4, 3 mM APMSF using a loose fitting homogenizer. Homogenates were mixed with an equal volume of 90% sucrose (w/v) in 10 mM Tris-HCl (pH 7.4), 150 mM NaCl and 5 mM EDTA (TBS) and then overlaid with 35% sucrose and 5% sucrose in TBS, and centrifuged. Ten fractions were collected from the top of the gradient. Lipid raft-containing light-scattering band just above the 5-35% sucrose interface was mainly collected in fraction 4. Gradient fractions were subjected to SDS-PAGE and Western blot-analysis. Note that lipid rafts were similarly prepared in both conditions.
Western blot-analysis
NECs were lysed by sonication (three 30-s bursts) in lysis buffer containing 1% Triton X-100, 10 mM Tris-HCl (pH 7.4), 150 mM NaCl, 5 mM EDTA, 5 µg/mL aprotinin, 2 mM Na3VO4, 3 mM APMSF. In some cases, NECs were starved in serum-free DMEM for 3 h, stimulated with mouse LIF (Chemicon) for 10 min, and then lysed. Protein concentration was measured by Protein Assay Kit (Bio-Rad). The lysates containing the same amount of proteins were applied to SDS-PAGE (5–20% or 4–20% polyacrylamide gel), and transferred to PVDF membrane (Amersham). Western-blot analysis was performed using antibodies to flotillin-1 (BD Bioscience), ß1 integrin (Chemicon), gp130, Janus kinase 1 (JAK1), STAT3, SH2 domain-containing tyrosine phosphatase (SHP-2), extracellular signal-regulated kinase (ERK) 1, ERK2, Ras (Santa Cruz Biotechnology), phospho-STAT3 or phospho-ERK (Cell Signalling).
Extraction and purification of GSLs
Extraction of total lipids and purification of GSLs from NECs were performed as previously described (Rokukawa et al. 1988). Purified gangliosides were subjected to TLC using precoated silica gel 60 high performance plates (Merck). For detection of gangliosides on TLC plates, resorcinol-HCl reagent was used.
DNA affinity precipitation
Biotin-conjugated double-stranded oligonucleotide containing a STAT3 binding element (SBE-oligo) was prepared by incubation of 5' biotinylated oligonucleotide (5'-GCT TTC CGA GAA GTC T-3', underline indicated STAT binding element) with anti-sense oligonucleotide (5'-AGA CTT CTC GGA AAG C-3') in 10 mM MgCl2 and 0.1 M NaCl for 2 min (65 °C). Lysates (containing 200 µg of proteins) prepared from NECs stimulated with LIF (25 ng/mL) were incubated with SBE-oligo (12 µM) in 500 µL of binding buffer containing 20 mM Tris-HCl (pH 8.0), 2 mM MgCl2, 40 mM NaCl, 1 mM EDTA, 10% glycerol, 0.1% NP-40, 1 mM DTT, 50 µg/mL BSA and 1 mg/mL poly (dI-dC) for 1 h at 4 °C with gentle agitation. Active STAT3 bound to biotin-SBE was pulled-down by gentle agitation with streptavidin-agarose for 30 min at 4 °C and subjected to SDS-PAGE followed by Western-blot using anti-STAT3 antibody.
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Acknowledgements |
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Footnotes |
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aPresent address: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, GA30912, USA
* Correspondence: E-mail: taga{at}kaiju.medic.kumamoto-u.ac.jp |
References |
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Received: 12 March 2004
Accepted: 8 June 2004
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