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1 KAN Research Institute, Inc., 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan
2 Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute 480-1195, Aichi, Japan
3 Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine/Faculty of Medicine, Kobe 650-0017, Hyogo, Japan
4 Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Osaka, Japan
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Abstract |
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vβ6 signaling from the basal surface-membrane or by inhibition of ROCK activity. On the contrary, HMW HA–CD44 signaling from the basal surface-membrane regulated the orientation of mitotic spindle axis to align oblique-perpendicular to the basal ECM. We also found that microtubule dynamics is required for HMW HA–CD44 mediated regulation of mitotic spindle orientation. Our findings thus provide a novel mechanism for the regulation of mitotic spindle orientation. |
Introduction |
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In this report, we show that signals generated from two distinct surface-membrane contacts, "bi-surface contacts," regulate the orientation of mitotic spindle axis. Using cultured normal human bronchial epithelial (NHBE) cells, we found that high molecular weight (HMW) hyaluronan (HA)–CD44-mediated signaling from the apical surface is required for aligning mitotic spindle parallel to the basal lining, whereas HMW HA–CD44-mediated signaling from the basal surface enhances oblique-perpendicular mitotic spindle alignment. HMW HA-dependent process to align the mitotic spindle parallel to the basal lining was dependent on microtubule dynamics and possibly reduction of ROCK activity, supporting the involvement of a microtubule plus-end dynamics and reduced tension of actomyosin contraction downstream of HMW HA–CD44 signaling pathway.
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Results |
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To address how extracellular signals regulate the orientation of mitotic spindle axis, we first developed a system that is depicted in Fig. 1. We obtained lateral view images of cells and scored the mitotic cell numbers by definition of the mitotic spindle axis angle (
°) relative to the axis angle parallel (0°) to the matrix plane (Fig. 1A). Distribution of mitotic spindle axis angles was scored and percentage was shown by section of 15° (Fig. 1B). Angles of " = 60 or more" were summed as " = 60–90" throughout the paper when presented. We first screened for cell lines that respond to mono-surface contact signals generated by the cell-basal ECM interaction to regulate the orientation of mitotic spindle axis. We tested NHBE cells, MCF and T47D breast cancer cell lines, all of which express and localize E-cadherin and occludin to respective cell–cell junction sites. All these cells showed spontaneous rotated mitotic spindle when cultured on poly-L-lysine. When NHBE cells were cultured in a semi-confluent manner on fibronectin, collagen I, laminin and vitronectin, cells on fibronectin showed increased population containing 0–15° axis angle and decreased population containing 30–90° axis angle of mitotic spindle (Fig. 1B). From this result and previous analyses performed in Drosophila neuroblasts (Bowman et al. 2006; Izumi et al. 2006; Siller et al. 2006), we set the criteria of " = 30 or more" axis angle as "rotated," and " < 30" axis angle as "non-rotated" mitotic spindle. Further analyses were performed by scoring cells with rotated mitotic spindle phenotype throughout this paper. Following this criterion, cells on fibronectin showed > 50% suppression in cells (mean 31.1–43.4 to 13.8) showing spontaneous rotated-spindle phenotype resulting in restoration of normal mitotic spindle orientation (Fig. 2A). By contrast, MCF7 and T47D cancer cell lines did not show significant effect on mitotic spindle orientation depending on integrin–interacting ECMs (Fig. 2B,C). From these results, we focused on NHBE cells as our analyzing system. When NHBE cells were analyzed with sparsely cultured no cell–cell contact condition, distribution pattern of mitotic spindle axis angles resembled that shown in Fig. 1B. On fibronectin, increased population containing 0–15° spindle axis angle and decreased population containing 30–90° spindle axis angle were observed (Fig. 3A). As a result, approximately 50% suppression of rotated-spindle phenotype (mean 39.4–48.6 to 17.7) was observed only on fibronectin (Fig. 3B). This result is consistent with the previous observation using HeLa cells that cell–cell contact was not a dominant driving force for the regulation of mitotic spindle orientation (Toyoshima & Nishida 2007a). We next tested which integrins are used to transduce fibronectin induced effect on the regulation of mitotic spindle orientation. We found that the effect by fibronectin was mediated through integrin vβ6, but not integrin β1 or β3, by use of established neutralizing antibodies (Fig. 3C). These results suggest that fibronectin–integrin vβ6 can provide a basal surface-membrane signaling cue to align mitotic spindle axis parallel to the ECM plane.
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In mammalian organs and in Drosophila airway system, apically secreted ECMs (aECMs) are shown to regulate ductal/tubular morphogenesis, including tube diameter and length control (Gakunga et al. 1997; Asselman et al. 2005; Tonning et al. 2006). Chitin, a polysaccharide consisting of N-acetylglucosamine, is one of the aECMs of which function is required for tracheal tube length and proper morphology (Luschnig et al. 2006; Wang et al. 2006). In human airway system, HA, a glycosaminoglycan polymer consisting of N-acetylglucosamine and glucronic acid, is found apically in the surface epithelium as well as the basal lamina (Monzon et al. 2006). As one of the invertebrate counterparts of HA is chitin, we tested the effect of HA and analyzed whether it can potentially regulate the orientation of mitotic spindle. HA is known to exist in various molecular weights (Toole 2004). We tested two distinct types of HA, a purified HMW (1000 kDa) and a LMW (10.4 kDa) by adding into the culture medium in a step-wise concentration. To eliminate integrin-mediated signaling from the basal membrane, NHBE cells were cultured on poly-L-lysine. Distribution of mitotic spindle axis angles was scored and percentage was shown in Fig. 4A. Of these two types of HA, addition of HMW HA showed increased population containing 0–15° spindle axis angle and decreased population containing 30–90° spindle axis angle (Fig. 4A) Consistently, approximately 50% (mean 35.1 to 15.4–17.0) suppression of cells showing rotated-spindle phenotype was observed at each HMW HA concentration (Fig. 4B). By contrast, LMW HA had subtle effect (mean 42.3 to 30.7–33.3) on the suppression of rotated-spindle phenotype (Fig. 4C). This result indicates that HMW HA regulates to restore normal mitotic spindle orientation parallel to the ECM plane. HA treatment itself did not affect progression of the cell cycle (data not shown). It also should be noted that our cell culture condition does not contain any serum, excluding any contamination of medium-derived ECM (see Experimental procedures). NHBE cells cultured on collagen I showed spontaneous rotated-spindle phenotype more than twofold (mean 35.2 to 13.8) compared to that on fibronectin (Fig. 2A). It has previously been shown that collagen I-integrin β1 signaling is required for suppressing rotated-spindle phenotype in HeLa cells (Toyoshima & Nishida 2007a). We tested whether HMW HA effect to align mitotic spindle axis parallel to the basal lining can be achieved with NHBE cells cultured on collagen I. We found that HMW HA added to the medium on cells cultured on collagen I suppressed rotated-spindle phenotype approximately 50% (40.2 to 19.7) to restore normal mitotic spindle orientation (Fig. 5A). However, up to 100-fold concentration of HA was required to achieve the suppressing effect that was seen when cultured on poly-L-lysine (Fig. 4B). This result strengths the role of HMW HA-mediated signaling on the restoration of normal mitotic spindle orientation. As restoration of normal mitotic spindle orientation was observed by fibronectin–integrin vβ6-mediated signaling, furthermore we tested whether HMW HA can synergistically suppress rotated-spindle phenotype. HMW HA failed to further suppress the effect achieved by fibronectin–integrin vβ6-mediated signaling (Fig. 5B). This result suggests that the effect by HMW HA or by fibronectin–integrin vβ6 from the basal surface for restoring normal mitotic spindle orientation is saturated.
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HMW HA–CD44 regulates orientation of mitotic spindle axis
It has been shown that HA can bind to a number of proteins, several of which are known or potential cell-surface receptors (Toole 2004). One of the HA-binding proteins CD44 is a one-time transmembrane glycoprotein which exists in two distinct forms, standard (CD44s) and variant (CD44v) forms (Ponta et al. 2003). CD44 is known to be involved in a number of physiological and pathological events including cell proliferation, growth, survival, migration/invasion and differentiation (Ponta et al. 2003; Toole 2004). We examined the involvement of CD44 on the effect of HMW HA. By use of an established CD44 function neutralizing antibody (anti-CD44), we tested whether the effect induced by HMW HA is abrogated by treatment with anti-CD44 into the medium. When NHBE cells were cultured on poly-L-lysine, in the presence of control IgG1, HMW HA led to approximately 40% suppression of cells (mean 36.3 to 21.8) showing rotated-spindle phenotype as expected (Fig. 6A). In contrast, blockage of CD44 function completely abrogated the suppression effect by HMW HA (Fig. 6A). Similar result was also obtained when cells were cultured on collagen I. With control IgG1, approximately 40% suppression of rotated mitotic spindle cells (mean 38.3 to 23.5) was observed by HMW HA treatment (Fig. 6B). In contrast, anti-CD44 completely blocked this suppressing effect (Fig. 6B). These results strengthen our idea that HMW HA–CD44 signaling pathway is a robust signaling pathway for restoration of normal mitotic spindle orientation.
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It is well established that microtubule functions, including capture of plus ends at appropriate sites, are required for the rotation of mitotic spindle (Kaltschmidt & Brand 2002; Ahringer 2003; Siegrist & Doe 2007). We tested whether microtubule dynamics is required in the process of HMW HA–CD44-regulated mitotic spindle orientation. We used nocodazole to abrogate microtubule dynamics. In order to treat as mild as possible, working concentrations were determined using T47D cells by the criterion that mitotic spindle orientation was affected but cell cycle progression was not (data not shown). When cells were mildly treated with 5 ng/mL nocodazole, cells showing rotated-spindle phenotype was at similar levels regardless of the addition of HMW HA (Fig. 8A). This result indicates that microtubule dynamics is required downstream of HMA HA–CD44-mediated signaling to restore normal mitotic spindle orientation.
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Discussion |
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We propose a rather simplified idea that "bi-surface-contact" signals regulate the orientation of mitotic spindle (Fig. 8B). It is that either integrins at the basal ECM-contacted membrane or CD44 at the apical HMW HA-contacted membrane generates most upstream signals to align mitotic spindle axis parallel to the basal surface and restore normal mitotic spindle orientation. In other words, our findings that the apical membrane can be the domain for generating signals for the regulation of mitotic spindle orientation, adds to the previously shown "mono-surface-contact" concept.
Our results show another unique feature in terms of "bi-surface-contact" signaling. HMW HA–CD44 signaling pathway is important not only from the apical membrane, but also from the basal membrane (Fig. 8B). In contrast to the effect from the apical membrane, HMW HA–CD44 signaling from the basal membrane enhances rotation of the mitotic spindle. This effect could not be overridden by HMW HA–CD44 signaling from the apical membrane (data not shown). This set of results implicate that if cells secrete HMW HA to the basal lamina, it will potentially initiate rotation of mitotic spindles regardless of the apical lumen existence of HMW HA. However, restored activity of integrin-mediated signaling at the basal membrane could circumvent this situation and suppress rotation of mitotic spindle. This notion may explain deficient phenotypes in skin epidermis and mammary gland observed with CD44 homozygous null mice (Yu et al. 2002; Bourguignon et al. 2006). HA is observed at the basal lamina of adult epidermis in mice, where CD44 expression coincides with (Tammi et al. 2005). Loss of CD44 may abrogate HA-mediated signaling from the basal surface and reduce the frequency of mitotic spindle rotation of epidermal basal cells, resulting in thinning of the epidermis in CD44-null mice (Bourguignon et al. 2006). Defect in mammary gland remodeling at lactating stage can be explained in the same context as basal surface-membrane HA–CD44 interaction was suggested to trigger mammary tissue branching (Xu & Yu 2003). It should be noted that exposure to the cell surface or secretion of de novo synthesized HA at the plasma membrane by HAS2, is not sufficient for inducing HA-receptor mediated signaling (Kultti et al. 2006). NHBE cells have been shown to synthesize and expose HA to the cell surface, and secrete HA to both the basal and apical membranes in vitro (Monzon et al. 2006). We also have observed apical cell-surface localization of self-exposed HA by indirect immunocytochemistry when cultured on poly-L-lysine and fibronectin, both of which at similar signal intensity (data not shown). As NHBE cells cultured on poly-L-lysine show rotated mitotic spindle in the absence of exogenous HMW HA, necessary CD44 clustering at exposed/secreted HA attachment sites is likely required in order to initiate exposed/secreted-HA–CD44 signaling. There is a possibility that de novo synthesized and cell surface-exposed HA by NHBE cells is not HMW HA.
It is unclear whether astral microtubules growing toward the cortex of (i) apical membrane, (ii) basal membrane, or (iii) both at metaphase are required for determining the orientation of mitotic spindle. It is clear from our results that microtubule dynamics is necessary for HMW HA–CD44 mediated regulation of mitotic spindle orientation. Our finding is consistent with the previous finding using HeLa cells showing that collagen I/fibronectin–integrin β1 mediated regulation of mitotic spindle orientation was abrogated by mild nocodazole treatment leading to the idea of requirement of microtubule dynamics in that context (Toyoshima & Nishida 2007a). Given the fact that our proposed signaling pathway is generated either by apical or basal or both membranes, the question of to which membrane region do growing microtubules are captured should be clarified. However, it still might differ depending on cell types and tissue types.
Finally, how our identified signals from two distinct membranes exert downstream remains to be clarified. Significant bodies of data have identified number of co-effectors and downstream effectors of CD44 (Ponta et al. 2003; Toole 2004). Known co-effectors EGF receptor and ErbB2 were not co-immunoprecipitated, and c-Met could not be detected in NHBE cells (T. Fujiwara, unpublished data). As we have laid out the foundation for further studies concerning the regulation of mitotic spindle orientation by HA–CD44 pathway, identifying downstream effectors of CD44 in this context emerges as the first step for future studies.
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Experimental procedures |
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Primary normal human bronchial epithelial cells (NHBE) were cultured in SAGM BulletKit (Cambrex, Walkersville, MD). This culture system does not contain fetal bovine serum (FBS) but uses 0.4% bovine pituitary extract, 0.5 ng/mL hEGF, 5 µg/mL insulin as a main source for cell growth. MCF-7 and T47D cell lines (ATCC, Rockville, MD) were cultured in RPMI1640 with L-glutamine (Invitrogen, Carlsbad, CA) supplemented with 10% heat inactivated FBS (Hyclone, Logan, UT), 1 mM sodium pyruvate (Invitrogen), 50 µM of 2-mercaptoethanol (Invitrogen) and 100 units/mL penicillin + 100 µg/mL streptomycin (Invitrogen). For cell synchronization, MCF-7 and T47Dcells were synchronized to G1/S phase by 1 or 2 mM thymidine treatment for 28 and 32 h, respectively. Synchronization was confirmed by FACS analysis, by which cells were trypsinized with 0.25% Trypsin/EDTA (Invitrogen). FACS data analyses were carried out using BD Cell quest Pro software. For each sample at least 5000 cells were analyzed. Four-well glass chambers (BD Biosciences, Bedford, MA) were coated with poly-L-lysine (P1524, Sigma, St Louis, MO), rat tail collagen I, human fibronectin, human vitronectin and mouse laminin (all BD Biosciences) by following manufactures’ instructions.
HA preparation and treatments
HMW HA (1000 kDa) and low molecular weight HA (10.4 kDa) were gifts from the Seikagaku Corporation (Tokyo, Japan). They were prepared from rooster comb with a combination of partial digestion with testicular hyaluronidase, and their molecular weights were determined by the viscometric assay as previously described (Koyama et al. 2007). HA treatment on NHBE cells was performed for 15 h with concentrations as indicated in the text and figures. High and low molecular weight HA-coated slides were prepared with concentrations of 50 µg/mL in combination with cationic poly-L-lysine (P1524, Sigma, St Louis, MO). Antibody blocking experiments were performed by simultaneous addition of 0.1 µg/mL monoclonal anti-CD44 antibody (Ab-2: Lab Vision, Fremont, CA) or mouse IgG1 negative control (Serotec, Oxford, UK) along with/without 5 µg/mL (medium added) or 50 µg/mL (coated) HA. For integrin blocking experiments, 0.1 µg/mL of monoclonal anti-integrin β1 (MAB2253, Chemicon), monoclonal anti-integrin β3 (MAB1957, Chemicon) and monoclonal anti-integrinvβ6 (MAB2077Z, Chemicon) were used simultaneously with fibronectin coating. Treatment with nocodazole (Sigma) was at 5 ng/mL and with Y-27632 (Calbiochem, San Diego, CA) was at 50 µM for 15 h along with/without 5 µg/mL HA.
Immunofluorescence imaging
For immunofluorescence imaging, cells were labeled with the following monoclonal antibodies: anti-CD44v3 (RD systems, Minneapolis, MN), anti-CD44v6 (RD systems), anti-CD44v4/5 (RD systems), anti-ZO-1 (Zymed, South San Francisco, CA) and anti--tubulin polyclonal antibody (Abcam, Cambridge, UK). For secondary antibodies, Alexa Fluor 488 or 568 goat anti-mouse IgG (Molecular Probes, Eugene, OR), Alexa Fluor 488 or 568 goat anti-rabbit IgG (Molecular Probes) were used to detect primary antibodies. Nuclei and chromosomes were labeled with DAPI (Sigma). Samples for immunofluorescence were fixed with 4% PFA/phosphate-buffered saline (PBS, pH 7.2–7.4) and permeabilized with 0.2% Triton X-100/PBS for 2 min. Fixed and permeabilized cells were blocked with 3% BSA/0.05% Tween 20 in PBS blocking solution. Antibodies were diluted in blocking solution. Cells were preserved in Vectashield mounting medium (H-1000, Burlingame, CA). Images were captured with laser-scanning confocal microscopes LSM510 (v. 2.3, Carl Zeiss, Germany) or Fluoview FV1000 (Olympus, Japan) systems.
Cell lysis and Western blotting
NHBE, SAEC and WI-38 cells were harvested on ice with ice-cold phosphate-buffered saline (pH 7.2–7.4) and were quickly frozen in liquid nitrogen. Cells were lysed for 15 min at 4 °C by rotation in lysis buffer containing 1% (v/v) Nonidet P-40, 0.5 mM EGTA, 5 mM sodium orthovanadate, 10% (v/v) glycerol, 50 mM HEPES (pH 7.4–7.5) and dissolved protease inhibitor cocktail tablets (Complete Mini, Roche). The lysate was clarified with centrifugation at 15 000 g for 15 min at 4 °C. An aliquot was kept for determining protein concentration by Lowry method (Bio-Rad, Hercules, CA). Lysates were added with SDS-containing denaturing buffer and boiled for 5 min at 95 °C.
For SDS-PAGE, the denatured samples were loaded onto 12% polyacrylamide gel. Proteins were transferred to nitrocellulose membranes by iblot TM gel transfer system (Invitrogen). Transferred membranes were blocked with 5% skim milk/0.05% Tween 20 in Tris-buffered saline. Detection was carried on by ECL Plus detection reagents (GE Healthcare). Detection was performed with monoclonal antibodies anti-CD44v3, anti-CD44v6, anti-CD44v4/5 (all RD systems) and polyclonal antibody anti-HCAM (H-300, Santa Cruz Biotechnology Inc, Santa Cruz, CA).
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Acknowledgements |
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Footnotes |
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* Correspondence: Email: t-fujiwara{at}kan.eisai.co.jp
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References |
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Received: 5 March 2008
Accepted: 10 April 2008
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