SciELO - Scientific Electronic Library Online

 
vol.35 issue2Phospholipid synthesis, diacylglycerol compartmentation, and apoptosisRegulation of Rho Family GTPases by Cell-Cell and Cell-Matrix Adhesion author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.35 no.2 Santiago  2002

http://dx.doi.org/10.4067/S0716-97602002000200015 

Biol Res 35: 231-238, 2002

Signaling triggered by Thy-1 interaction with ß3 integrin on astrocytes is an essential step towards unraveling neuronal Thy-1 function

ANA MARIA AVALOS*, CECILIA V. LABRA*, ANDREW F.G. QUEST^ AND LISSETTE LEYTON*#

Programs of *Morphology and ^Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile

ABSTRACT

Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence, Thy-1 function remains largely obscure in the absence of a defined ligand. Recently described evidence that Thy-1 interacts with ß3 integrin on astrocytes will be discussed. Thy-1 binding to ß3 integrin triggers tyrosine phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal adhesion formation, cell attachment and spreading. Thy-1 has been reported to modulate neurite outgrowth by triggering a cellular response in neurons. However, our data indicate that Thy-1 can also initiate signaling events that promote adhesion of adjacent astrocytes to the underlying surface. Preliminary results suggest that morphological changes observed in the actin cytoskeleton of astrocytes as a consequence of Thy-1 binding is mediated by small GTPases from the Rho family. Our findings argue that Thy-1 functions in a bimodal fashion, as a receptor on neuronal cells and as a ligand for ß3 integrin receptor on astrocytes. Since Thy-1 is implicated in the inhibition of neurite outgrowth, signaling events in astrocytes are likely to play an important role in this process.

Key terms: (Thy-1 ligand/integrins/GPI-anchored proteins/astrocytes/focal adhesion)

(1) Abbreviations used in this paper: CNS, central nervous system; ECM, extracellular matrix; FAs, focal adhesions; GAPs, GTPase activating proteins; GEFs, guanine nucleotide exchange factors; GPI, glycosyl-phosphatidylinositol; IgSF, immunoglobulin superfamily; SF, stress fibers.

NEURON-ASTROCYTE INTERACTIONS

In vertebrates, a large number of neurons migrate remarkably long distances to form the neuronal system. As a consequence, different classes of cells come to reside in specific layers that form the complex neuronal circuitry. Migration, guidance, signaling cues, and specific cell-cell interactions are key events to the formation of such circuitry. Reportedly, migration of 80_90% of the billions of neuronal precursors in mammalian cortex occurs along glial fibers. Thus, during development of the nervous system interactions between neurons and glia are crucial events (Hatten, 1999). In the vertebrate nervous system, glial cells are divided into two major classes: microglia and macroglia. While microglia are phagocytes that become activated in a number of diseases, macroglia include predominantly three cell types: oligodendrocytes, Schwann cells and astrocytes. Oligodendrocytes and Schwann cells insulate axons forming a myelin sheath, while astrocytes, the most numerous type of glia, are traditionally thought to provide nerve cells with structural support, nutrients and protection.

Until recently, it was believed that signaling was mainly a function attributed to nerve cells. However, there is increasing evidence indicating that bidirectional signaling between neurons and astrocytes exists. Furthermore, neuron-independent signaling in astrocytes has also been reported, indicating that astrocytes should be considered to play a far more dynamic role in the brain than once thought (Araque et al., 1999, 2001; Leyton et al., 2001; LoTurco, 2000; Nett et al., 2002; Vesce et al., 1999). Such neuron-astrocyte intercommunication also plays an essential role in repairing neuronal connections after injury.
Plasticity, the ability of one group of neurons to take over the function of another injured group, is much less prominent in the adult central nervous system (CNS)(1), in part, due to the necessary formation of the glial scar. In the CNS, astrocytes display a stellate, process-bearing morphology. When exposed to blood-borne factors after brain damage, they undergo changes in shape, converting from the stellate to a fibroblast-like morphology, coincident with the initiation of migration and proliferation required for glial scar formation. This so-called "reactive gliosis," although necessary to protect the brain from secondary lesions (Ridet et al., 1997), has long been considered a major impediment to neuronal regeneration in the CNS. Crushed or cut nerve fibers in the adult CNS often react with spontaneous but unsuccessful regenerative sprouting. Such lack of success is due to the presence of specific inhibitory proteins that block neurite outgrowth. These proteins include the neuronal growth inhibitory molecules Nogo (Huber and Schwab, 2000), myelin-associated glycoprotein (Shen et al., 1998), the growth cone collapsing Semaphorins/neuropilins (Skaper et al., 2001), plasma membrane heparan-sulphate and condroitin-sulphate type-proteoglycans (Nieto-Sampedro, 1999) and the neuronal glycoprotein Thy-1 (Tiveron et al., 1992; 1994).

In recent years, we have focused on identifying a ligand for Thy-1 in astrocytes and investigating the signaling events triggered as a consequence of such receptor-ligand interaction with the underlying notion that these events are likely to be relevant to understanding fundamental aspects of astrocyte/neuron interaction. Insight gained from this analysis are discussed here.

Thy-1 structure and function

Thy-1 is a member of the immunoglobulin superfamily (IgSF), one of the major cell adhesion families. It is expressed as a glycosyl-phosphatidylinositol (GPI)-anchored protein in various cell types, particularly those of the T-cell lineage and the neuronal system. Thy-1 is one of the most abundant neuronal glycoproteins in mammals and its expression is regulated to exclude it from regions of axonal growth, thus controlling neuronal differentiation (Morris, 1992; Xue et al., 1991; Labra et al., 2001). Although implicated in cell adhesion and inhibition of neurite outgrowth, Thy-1 function has remained largely unclear due to the long awaited discovery of its ligand molecule. Furthermore, the relevance of Thy-1 in the nervous system has been questioned by the finding that Thy-1-deficient mice neither show reproductive or health deficiencies nor neurological abnormalities. However, this may be the consequence of compensatory mechanisms, since deficiency of other molecules involved in neuronal adhesion also result in modest effects in vivo (reviewed by Hynes, 1996). Thy-1 deficient mice are not affected in their spatial learning capacity, although long-term potentiation is strongly inhibited in the dentate gyrus of the hippocampus (Nosten-Bertrand et al., 1996). These mice also lack a key survival behavior, namely, the normal ability of mice in a colony to learn from one another which foods are safe to eat (Mayeux-Portas et al., 2000). Thus, from an evolutionary point of view, the presence of Thy-1 in the neuronal system seems important, although the reason why such high levels are required in the nervous system remains a mystery.

Seeking a ligand for Thy-1

Potential carriers of Thy-1 ligand(s) include thymic epithelial cells (Hueber et al., 1992), murine fibroblasts (Johnson et al., 1993) and astrocytes (Dreyer et al., 1995). Furthermore, an astrocytic binding site for neuronal Thy-1 was described, whereby the interactions between Thy-1 and the putative ligand were responsible for modulating neurite outgrowth (Tiveron et al., 1992; 1994). Thus, we sought to identify a Thy-1 ligand in astrocytes.

Other known cell adhesion molecules from the IgSF involved in modulating neurite outgrowth include the transmembrane glycoprotein L1. L1 plays an important role in brain development promoting neurite outgrowth by at least two mechanisms: homophilic L1-L1 interactions and also heterophilic L1-integrin interactions, in which case aVb3 integrin is the L1 binding partner (Montgomery et al., 1996; Yip et al., 1998). Integrins are a family of cell-surface glycoproteins comprised of two different subunits (a and b), that form heterodimers and act as receptors for either extracellular matrix (ECM) proteins or cell-surface molecules present on other cells (reviewed by Juliano, 2002). Integrins recognize common sequences found in ECM molecules such as the RGD tripeptide (Arg-Gly-Asp). This motif is present in the Ig6 loop of L1 and is recognized by aVb3 (Yip et al., 1998). Based on these findings, we tested the hypothesis that Thy-1 might also interact with integrins, and started our analysis by identifying an RGD-related peptide in Thy-1 corresponding to an RLD tripeptide. This particular sequence serves as a recognition sequence for aVb3 and aMß2 integrins (Ruoslahti, 1996), but since the latter is found exclusively in cells of the leukocyte lineage,aVb3 represented our best candidate binding partner for Thy-1 in astrocytes.

Results of such studies have been published recently (Leyton et al., 2001). There, we described a novel method to study cell-cell adhesion using adherent astrocytes and a thymoma cell line (EL-4) that abundantly expresses Thy-1. As a control for non-specific binding, a mutant cell line which does not express Thy-1 on its surface (EL-4-f) was used. Both Thy-1+ and Thy-1- thymoma cells were stained with two different colored cell trackers (TM, Molecular Probes). These cells were incubated for 20 min with the astrocytes and then gently washed to remove non-specifically bound cells. Using confocal microscopy and Adobe Photoshop to quantitate the number of green and red cells, a relative binding index was calculated as the ratio between Thy-1+/Thy-1- cells. Results obtained indicate that Thy-1+ cell binding is 5-fold enhanced when compared to binding of Thy-1- cells. These results were independent of the cell tracker employed to label the cells (Leyton, L., unpublished results). Binding was blocked by antibodies either to Thy-1 or integrin b3, by RGD-related peptides or Thy-1-Fc fusion proteins, but neither by antibodies to the T cell receptor nor to integrin b1, inactive RGE peptides or the mutated Thy-1(RLE)-Fc fusion protein. Taken together, these data suggest that the astrocytic molecule involved in Thy-1 binding is an integrin containing the b3 subunit. Given the ubiquitous location of aVb3, we hypothesize that this is the integrin mediating Thy-1 binding to astrocytes.

Interactions of aVb3 integrin with the ECM have been implicated in a wide variety of functions, including implantation, angiogenesis, bone remodeling, and tumor progression (Bader et al., 1998; Hodivala-Dilke et al., 1999; Hynes et al., 1999; Sutherland et al., 1993; Varner et al., 1995; Varner and Cheresh, 1996). These interactions also trigger focal adhesion (FA) formation which are sites of strong adhesion to the ECM that provide a structural link to the actin cytoskeleton. Integrins serve as a bridge between the ECM and FA sites thereby favoring cell adhesion and activation of various intracellular signaling pathways required for FA formation. Ultimately, these interactions culminate in cytoskeletal reorganization, bundling of actin filaments leading to the formation of stress fibers (SF) and altered cell behavior (Burridge and Chrzanowska-Wodnicka, 1996; Sastry and Burridge, 2000).

Thus, in our studies we investigated the role of Thy-1-aVb3 integrin interaction on astrocyte morphology and signaling. The results indicate that binding of Thy-1 to aVb3 stimulates the assembly of FAs and SF in astrocytes, as well as cell adhesion and spreading. Also, high levels of tyrosine phosphorylation were found in proteins implicated in FA formation, and such proteins were recruited to the sites of complex formation. By indirect immunofluorescence, enhanced phosphorylation on tyrosine was also observed when either prompting astrocytes to adhere to Thy-1-Fc-coated coverslips or stimulating already adherent cells with Thy-1-Fc coated beads (Leyton et al., 2001).

Such enhanced phosphorylation was not observed when using the Thy-1(RLE)-Fc fusion protein either on the coverslip (Leyton et al., 2001) or coated on the beads (Figure 1), highlighting the relevance of the RLD motif in Thy-1 induced response.

Fig. 1: Astrocytes adhered to coverslips were treated in the absence or presence of Thy-1-Fc coated Prot-A-Agarose beads. Mutated (RLE) and non mutated (RLD) forms of Thy-1 were used. After 10 min incubation, beads were removed and cells fixed with 4% p-formaldehyde. Immunofluorescence was done using anti-phosphotyrosine (4G10) mAbs detected with anti-mouse IgG conjugated to FITC and phalloidin to stain SF (more details in Leyton et al., 2001). Increased phosphotyrosine in FAs, enhanced number and size of FAs and more robust SF were observed in Thy-1(RLD)-Fc stimulated cells. However, Thy-1(RLE) treated cells show levels of phosphotyrosine that are more comparable to non-treated cells.

The assembly of FAs is regulated by RhoA, a low molecular weight GTPase (Hall, 1998; Ridley and Hall, 1992). Within the Rho family, Rac and Cdc42 also stimulate assembly of multimolecular complexes, but into smaller more transient structures, often referred to as focal complexes (Nobes and Hall, 1995). RhoA, Rac and Cdc42 all influence cell migration. However, while Rac and Cdc42 promote cell extension in the form of lamellipodia or filopodia, respectively, RhoA stimulates contraction and the assembly of SF (Burridge and Chrzanowska-Wodnicka, 1996; Hall, 1998). Although baseline RhoA activity is needed for cell migration, high activity is inhibitory, in part, because of antagonizing forward protrusion (Arthur and Burridge, 2001; Rottner et al., 1999). Like other G proteins, members of the Rho family are active when GTP is bound and inactive with GDP bound. Activation is promoted by guanine nucleotide exchange factors (GEFs) that exchange GTP for GDP. Intrinsic GTPase activity of these proteins hydrolyzes bound GTP and terminates their interaction with downstream effectors. The GTPase activity is stimulated by GTPase activating proteins (GAPs). Many soluble factors (e.g. LPA, sphingosine-1-phosphate, thrombin, etc.) have been identified that elevate the activity of Rho family members. These soluble factors interact either with G protein coupled receptors or receptor tyrosine kinases that then signal to GEFs. However, recently, it has become apparent that many cell adhesion molecules, including integrins, also regulate the activity of RhoA, Rac1 and Cdc42 (Barry et al., 1997; Ren et al., 1999). Integrin-mediated adhesion to fibronectin stimulates activation of Rac1 and Cdc42, but causes an initial decrease in RhoA activity (Arthur et al., 2002; Ren et al., 1999). Burridge and coworkers have demonstrated that integrin engagement with soluble RGD peptides is sufficient to cause depression in RhoA activity and that this involves Src activation and subsequent phosphorylation and activation of p190RhoGAP (Arthur et al., 2000; 2002).

As many similarities were apparent between responses observed in FN-stimulated fibroblasts and Thy-1 activated astrocytes, the idea that the small G protein Rho, implicated in signaling events downstream of integrins, may be important in astrocytes was appealing. Our preliminary results indicate that inhibition of Rho kinase, one of the downstream effectors of RhoA, by using a Rho kinase inhibitor (Y27632) prevents Thy-1-induced FA formation (Figure 2). Such results are indicative of Rho involvement in the process triggered by Thy-1. These and other findings concerning Rho involvement will be discussed at this Symposium.


Fig. 2: Astrocytes grown on coverslips were treated (or not) with 50 µM of Rho kinase inhibitor (Y27632) for 30 min prior to stimulation with Thy-1-Fc coated Prot-A-Agarose beads. Stimulation and immunofluorescence were done as indicated in Figure 1, except that FAs were stained with anti-paxillin Abs. Treatment with Rho kinase inhibitor significantly decreased SF and FA. Here, FAs are seen as small dots at the end of SF and thus resemble more focal complex structures. In non-stimulated, non-inhibitor treated cells, focal complexes and FAs are formed, of which the latter is identified by their increased size and elongated structures. SFs are also visible in these cells. When treating with Thy-1 beads, FAs are enhanced in size and number. A better marked actin cytoskeleton is also observed in treated cells. Stimulation caused by Thy-1-Fc beads was not observed in Y27632 treated cells, indicating Rho-dependence.

We consider these studies to be relevant to understanding aspects of astrocyte/neuron interaction, since after brain injury astrocytes suffer morphological changes that are accompanied by gain of actin SF and FAs, processes in which Rho GTPases have been implicated (Ridley and Hall, 1992). Astrocyte exposure to LPA coming from blood, could explain in part the morphological changes observed. However, it has also been reported that during brain injury or stroke, there is an upregulation of aVb3 on astrocytes (Ellison et al., 1999). We suspect that changes in the engagement of this integrin with Thy-1 may affect astrocyte migration and/or proliferation, thereby contributing to glial scar formation following brain injury. This process is known to impede neuronal regeneration. Thus, upregulation of aVb3 on astrocytes, elevated expression of neuronal Thy-1 and subsequent interaction of the two proteins may provide a basis to understand the inhibitory role that Thy-1 is thought to play in controlling adult neurite outgrowth.

ACKNOWLEDGEMENTS

This work is supported by Fundación Andes (Grant C-13680/4 to LL), Fogarty-NIH (Grant 1R03TW006024-01 to LL), Fondecyt Grants # 1990893 and #1020585 to AQ) and ICGEB (Grant CRP/CH100-05 to AQ). A.M.A. was supported by a Ph.D. fellowship granted by Conicyt and C.V.L. by ICGEB (Grant CRP/CH100-05 to AQ).

REFERENCES>

ARAQUE A, PARPURA V, SANZGIRI RP, HAYDON PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208-215         [ Links ]

ARAQUE A, CARMIGNOTO G, HAYDON PG (2001) Dynamic signaling between astrocytes and neurons. Annu Rev Physiol 63:795-813         [ Links ]

ARTHUR WT, BURRIDGE K (2001) RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol Biol Cell 12:2711-2720         [ Links ]

ARTHUR WT, PETCH LA, BURRIDGE K (2000) Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Curr Biol 10:719-722         [ Links ]

ARTHUR WT, NOREN NK, BURRIDGE K (2002) Regulation of Rho family GTPases by cell-cell and cell-matrix adhesion. Biol Res 35: 239-246         [ Links ]

BADER BL, RAYBURN H, CROWLEY D, HYNES RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all av integrins. Cell 95:507-519         [ Links ]

BARRY ST, FLINN HM, HUMPHRIES MJ, CRITCHLEY DR, RIDLEY AJ (1997) Requirement for Rho in integrin signaling. Cell Adhes Commun 4:387-398         [ Links ]

BURRIDGE K, CHRZANOWSKA-WODNICKA M (1996) Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol 12:463-518         [ Links ]

DREYER EB, LEIFER D, HENG JE, MCCONNELL JE, GORLA M, LEVIN LA, BARNSTABLE CJ, LIPTON SA (1995) An astrocytic binding site for neuronal Thy-1 and its effects on neurite outgrowth. Proc Natl Acad Sci USA 92:11195-11199         [ Links ]

ELLISON JA, BARONE FC, FEUERSTEIN GZ (1999) Matrix remodeling after stroke. De novo expression of matrix proteins and integrin receptors. Ann N Y Acad Sci 890:204-222         [ Links ]

HALL A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509-514         [ Links ]

HATTEN ME (1999) Central nervous system neuronal migration. Annu Rev Neurosci 22:511-539         [ Links ]

HODIVALA-DILKE KM, MCHUGH KP, TSAKIRIS DA, RAYBURN H, CROWLEY D, ULLMAN-CULLERE M, ROSS FP, COLLER BS, TEITELBAUM S, HYNES RO (1999) Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229-238         [ Links ]

HUBER AB, SCHWAB ME (2000) Nogo-A, a potent inhibitor of neurite outgrowth and regeneration. Biol Chem 381:407-419         [ Links ]

HUEBER AO, PIERRES M, HE HT (1992) Sulfated glycans directly interact with mouse Thy-1 and negatively regulate Thy-1 mediated adhesion of thymocytes to thymic epithelial cells. J Immunol 148:3692-3699         [ Links ]

HYNES RO (1996) Targeted mutations in cell adhesion genes: what have we learned from them? Dev Biol 180:402-412         [ Links ]

HYNES RO, BADER BL, HODIVALA-DILKE K (1999) Integrins in vascular development. Braz J Med Biol Res 32:501-510         [ Links ]

JOHNSON R, LANCKI D, FITCH F (1993) Accessory molecules involved in antigen-mediated cytolysis and lymphokine production by cytotoxic T lymphocyte subsets. J Immunol 151:2986-2999         [ Links ]

JULIANO RL (2002) Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin- superfamily members. Annu Rev Pharmacol Toxicol 42:283-323         [ Links ]

LABRA CV, HETZ CA, QUEST AFG, LEYTON L (2001) Studies of the functional role of Thy-1 and caveolin-1 in neuronal differentiation. Biol Res 34:R71         [ Links ]

LEYTON L, SCHNEIDER P, LABRA CV, RÜEGG C, HETZ CA, QUEST AFG, BRON C (2001) Thy-1 binds to the integrin ß3 on astrocytes and triggers formation of focal contact sites. Curr Biol 11:1028-1038         [ Links ]

LOTURCO JJ (2000) Neural circuits in the 21st century: Synaptic networks of neurons and glia. Proc Natl Acad Sci USA 97:8196-8197         [ Links ]

MAYEUX-PORTAS V, FILE SE, STEWART CL, MORRIS RJ (2000) Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food. Curr Biol 10:68-75         [ Links ]

MONTGOMERY AM, BECKER JC, SIU CH, LEMMON VP, CHERESH DA, PANCOOK JD, ZHAO X, REISFELD RA (1996) Human neural cell adhesion molecule L1 and rat homologue NILE are ligands for integrin alpha v beta 3. J Cell Biol 132:475-485         [ Links ]

MORRIS RJ (1992) Thy-1, the enigmatic extrovert on the neuronal surface. BioEssays 14:715-722         [ Links ]

NETT WJ, OLOFF SH, MCCARTHY KD (2002) Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J Neurophysiol 87:528-537.         [ Links ]

NIETO-SAMPEDRO M (1999) Neurite outgrowth inhibitors in gliotic tissue. Adv Exp Med Biol 468:207-224         [ Links ]

NOBES CD, HALL A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53-62         [ Links ]

NOSTERN-BERTRAND M, ERRINGTON ML, MURPHY KP, TOKUGAWA Y, BARBONI E, KOZLOVA E, MICHALOVICH D, MORRIS RG, SILVER J, STEWART CL, BLISS TV, MORRIS RJ (1996) Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature 379:826-829         [ Links ]

REN XD, KIOSSES WB, SCHWARTZ MA (1999) Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J 18:578-585         [ Links ]

RIDET JL, MALHOTRA SK, PRIVAT A, GAGE FH (1997) Reactive astrocytes: cellular and molecular cues to biological function [published erratum appears in Trends Neurosci 1998 Feb;21(2):80]. Trends Neurosci 20:570-577         [ Links ]

RIDLEY AJ, HALLl A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389-399         [ Links ]

ROTTNER K, HALL A, SMALL JV (1999) Interplay between Rac and Rho in the control of substrate contact dynamics. Curr Biol 9:640-648         [ Links ]

RUOSLAHTI E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697-715         [ Links ]

SASTRY SK, BURRIDGE K (2000) Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp Cell Res 261:25-36         [ Links ]

SHEN YJ, DEBELLARD ME, SALZER JL, RODER J, FILBIN MT (1998) Myelin-associated glycoprotein in myelin and expressed by Schwann cells inhibits axonal regeneration and branching. Mol Cell Neurosci 12:79-91         [ Links ]

SKAPER SD, MOORE SE, WALSH FS (2001) Cell signaling cascades regulating neuronal growth-promoting and inhibitory cues. Prog Neurobiol 65:593-608         [ Links ]

SUTHERLAND AE, CALARCO PG, DAMSKY CH (1993) Developmental regulation of integrin expression at the time of implantation in the mouse embryo. Development 119:1175-1186         [ Links ]

TIVERON MC, BARBONI E, PLIEGO RIVERO FB, GORMLEY AM, SEELEY PJ, GROSVELD F, MORRIS RJ (1992) Selective inhibition of neurite outgrowth on mature astrocytes by Thy-1 glycoprotein. Nature 355:745-748         [ Links ]

TIVERON MC, NOSTEN-BERTRAND M, JANI H, GARNETT D, HIRST EM, GROSVELD F, MORRIS RJ (1994) The mode of anchorage to the cell surface determines both the function and the membrane location of Thy-1 glycoprotein. J Cell Sci 107:1783-1796         [ Links ]

VARNER JA, BROOKS PC, CHERESH DA (1995) REVIEW: the integrin alpha V beta 3: angiogenesis and apoptosis. Cell Adhes Commun 3:367-374         [ Links ]

VARNER JA, CHERESH DA (1996) Integrins and cancer. Curr Opin Cell Biol 8:724-730         [ Links ]

VESCE S, BEZZI P, VOLTERRA A (1999) The highly integrated dialogue between neurons and astrocytes in brain function. Sci Prog 82:251-270         [ Links ]

XUE GP, RIVERO BP, MORRIS RJ (1991) The surface glycoprotein Thy-1 is excluded from growing axons during development: a study of the expression of Thy-1 during axogenesis in hippocampus and hindbrain. Development 112:161-176         [ Links ]

YIP PM, ZHAO X, MONTGOMERY AMP, SIU C-H (1998) The Arg-Gly-Asp motif in the cell adhesion molecule L1 promotes neurite outgrowth via interaction with aVß3 integrin. Mol Biol Cell 9:277-290         [ Links ]

Corresponding author: Lisette Leyton, Ph.D. Independencia 1027. Program of Morphology. ICBM, Faculty of Medicine, University of Chile, Santiago-CHILE. Telephone/Fax: 56-2-738-2015. e-mail: lleyton@machi.med.uchile.cl

Received: May 30, 2002. In revised form: June 14, 2002. Accepted: June 21, 2002

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License