Laminin A
At gastrulation in the sea urchin embryo dramatic cell adhesion changes contribute to primary
mesenchyme cell ingression movements and to cell rearrangements during archenteron invagination. At
ingression, quantitative adhesion assays have previously demonstrated that primary mesenchyme cells
(PMCs) change their affinity for neighboring cells, for a fibronectin-like substrate, and for the hyaline
layer. To investigate the molecular basis for these and other differential cell affinities at gastrulation,
an integrin has been identified that appears to be responsible for specific alterations in cell-substrate
adhesion to laminin. During early cleavage stages blastomeres adhere poorly to laminin substrates.
Around hatching there is a large increase in the ability of blastomeres to bind to laminin and this
increase correlates temporally with the expression of an integrin on the basal surface of all blastomeres.
PMCs, after undergoing their epithelial-mesenchymal transition, have a strongly reduced affinity for
laminin relative to ectoderm cells and, correspondingly, do not stain for the presence of the integrin. The alpha integrin cDNA from Lytechinus variegatus has been identified by RT-PCR. Overlapping clones were
obtained from a midgastrula cDNA library to provide a complete sequence for the integrin. The
composite cDNA encoded a protein that is most similar to the alpha5 subgroup of vertebrate
integrins, but there was not a definitive vertebrate integrin homolog. Northern blots and Western
immunoblots show that the sea urchin integrin, which has been named alphaSU2, is present in eggs
and during all stages of development. Immunolocalization with specific polyclonal antibodies show
that alphaSU2 first appears on the basal cell surface of epithelia at the midblastula stage, at a time
correlating with the increase in adhesive affinity for laminin. The protein remains at high levels on the
basal surface of ectoderm cells but is temporarily reduced or eliminated from endoderm cells during
their convergent-extension movements. To confirm integrin binding specificity, alphaSU2 was
transfected into an alpha-integrin-deficient CHO cell line. alphaSU2-expressing CHO cells bind well
to isolated sea urchin basal lamina and to purified laminin. The transfected cells bind weakly or not at
all to fibronectin, type I collagen, and type IV collagen. This is consistent with the hypothesis that
alphaSU2 integrin functions by binding epithelial cells to laminin in the basal lamina. In vivo, modulation
of alphaSU2 integrin expression correlates with critical adhesive changes during cleavage and
gastrulation. Thus, this protein appears to be an important contributor to the morphogenetic
rearrangements that characterize gastrulation in the sea urchin embryo (Hertzler, 1999).
Receptors of the integrin family are expressed by every cell type and are the primary means by which cells interact with the extracellular matrix. The control of integrin expression affects a wide range of developmental and cellular processes, including the regulation of gene expression, cell adhesion, cell morphogenesis and cell migration. The concentration of substratum-bound ligand (laminin) post-translationally regulates the amount of receptor (alpha6beta1, integrin) expressed on the surface of sensory neurons (see Drosophila Myospheroid). When ligand availability is low, surface amounts of receptor increase, whereas integrin RNA and total integrin protein decrease. Ligand concentration determines surface levels of integrin by altering the rate at which receptor is removed from the cell surface. Furthermore, increased expression of integrin at the cell surface is associated with increased neuronal cell adhesion and neurite outgrowth. These results indicate that integrin regulation maintains neuronal growth-cone motility over a broad range of ligand concentrations, allowing axons to invade different tissues during development and regeneration (Condic, 1997).
The development of the heart from a single heart tube to a four chambered organ with two separated unidirectional flows is a highly complex process. Events like looping, septation, tissue remodelling, and development of valves take place at a time when the heart is already pumping. The ability of cells to migrate in such a dynamic environment, and to adhere to one another and to their extracellular matrix is crucial. Integrins and extracellular matrix components have already been implicated in this process. The differential expression of the alpha-6 integrin subunit was studied during late murine heart development, e.g., in the process from looping to the end of septation. A constant and high expression of alpha-6 occurs in the atrial myocardium and a decrease in expression takes place in the ventricular trabecular myocardium. The compact myocardial wall and the ventricular septum do not express alpha-6, except for the myocardium of the distal outflow tract at early stages. The expression of this integrin subunit is described in the endocardial cushions that contribute to the development of the atrioventricular and semilunar valves. A role is proposed for the alpha-6-beta-1 laminin receptor in the adhesion of cells to their extracellular matrix at sites of high stress due to cardiac contraction or shear stress induced by blood flow. This study suggests a distinct role for alpha-6-beta-1 in the heart and provides insight concerning the probable, and no doubt vital roles of integrins and their extracellular matrix ligands during embryonic development (Hierck, 1997).
F9 embryonal carcinoma cells treated with retinoic acid differentiate in monolayer into parietal endoderm (PE) or in suspension into embryoid bodies with an outer layer of visceral endoderm (VE) surrounding a core of largely undifferentiated cells. Cell-extracellular matrix interactions mediated by the beta 1 integrins play a critical role in the differentiation and migration of PE. The pattern of expression and function of the integrin alpha 6 beta 1 was studied during the differentiation of F9 cells into VE and PE. F9 cells express integrin subunits alpha 3, alpha 5, alpha 6, and beta 1. Cell adhesion and migration assays demonstrate that alpha 6 beta 1 is the major laminin receptor in undifferentiated F9 cells as well as F9-derived PE cells. However, the amount of alpha 6 protein decreases significantly upon F9 cell differentiation into either VE or PE. In contrast, the amount of steady-state alpha 6 message stays constant before and after F9 cell differentiation, suggesting that the down-regulation of alpha 6 beta 1 occurs post-transcriptionally. Two alpha 6 isoforms are generated by alternative RNA processing. While alpha 6B is the major mRNA isoform before and after F9 cell differentiation, alpha 6A mRNA is weakly expressed in undifferentiated F9 cells and is substantially increased following F9 differentiation into PE. An increase in alpha 6A and a dramatic decrease in alpha 6B protein occurs following PE differentiation. Whereas the stability of alpha 6B protein is unaltered, synthesis of alpha 6B protein is decreased at least threefold following PE differentiation. Further experiments demonstrate that alpha 6A localizes to focal contacts in PE cells. The switch from alpha 6B to alpha 6A and the localization of alpha 6A at focal contacts correlate with the acquisition of PE cell motility, which suggests distinct functions for the two alpha 6 isoforms (Jiang, 1995).
Many aspects of myogenesis are believed to be regulated by myoblast interactions with specific components of the extracellular matrix. For example, laminin has been found to promote adhesion, migration, and proliferation of mammalian myoblasts. Based on affinity chromatography, the alpha7beta1 integrin has been presumed to be the major receptor mediating myoblast interactions with laminin. A monoclonal antibody, O26, was prepared that specifically reacts with both the X1 and the X2 extracellular splice variants of the alpha7 integrin chain. This antibody completely and selectively blocks adhesion and migration of rat L8E63 myoblasts on laminin-1, but not on fibronectin. In contrast, a polyclonal antibody to the fibronectin receptor, alpha5beta1 integrin, blocks myoblast adhesion on fibronectin, but not on laminin-1. The alpha7beta1 integrin also binds to a mixture of laminin-2 and laminin-4, the major laminin isoforms in developing and adult skeletal muscle, but O26 is a much less potent inhibitor of myoblast adhesion on the laminin-2/4 mixture than on laminin-1. Based on affinity chromatography, it is suggested that this may be due to higher affinity binding of alpha7X1 to laminin-2/4 than to laminin-1 (Crawley, 1997).
Two distinct populations of myoblasts, distinguishable by alpha7 integrin expression have been hypothesized to give rise to two phases of myofiber formation in embryonic limb development. Alpha7 integrin is detectable far earlier than previously reported on both 'primary' and 'secondary' lineage myoblasts and myofibers. An antibody (1211) that recognizes an intracellular epitope allows detection of alpha7 integrin previously missed, using an antibody (H36) that recognizes an extracellular epitope. When myoblasts were isolated and cultured from different developmental stages, H36 only detects alpha7 integrin that is in direct contact with its ligand, laminin. Moreover, alpha7 integrin detection by H36 is reversible and highly localized to subcellular points of contact between myoblasts and laminin-coated 2.8-mm microspheres. Prior to secondary myofiber formation in limb embryogenesis, laminin is present but not in close proximity to clusters of primary myofibers that expressed alpha7 integrin detected by antibody 1211, using deconvolution microscopy. These results suggest that the timing of the interaction of preexisting alpha7 integrin with its ligand, laminin, is a major determinant of allosteric changes that result in an activated form of alpha7 integrin capable of transducing signals from the extracellular matrix commensurate with secondary myofiber formation (Blanco-Bose, 2001).
Functional studies of the alpha6beta4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton. The function of the alpha6beta4 integrin was examined in clone A cells, a colon carcinoma cell line that expresses alpha6beta4 but no alpha6beta1 integrin and exhibits dynamic adhesion and motility on laminin-1. Time-lapse videomicroscopy of clone A cells on laminin-1 reveal that their migration is characterized by filopodial extension and stabilization followed by lamellae that extend in the direction of stabilized filopodia. A function-blocking mAb specific for the alpha6beta4 integrin inhibits clone A migration on laminin-1. This mAb also inhibits filopodial formation and stabilization and lamella formation. The alpha6beta4 integrin is localized as discrete clusters in filopodia, lamellae, and retraction fibers. Although beta1 integrins are also localized in the same structures, a spatial separation of these two integrin populations is evident. In filopodia and lamellae, a striking colocalization of the alpha6beta4 integrin and F-actin is seen. An association between alpha6beta4 and F-actin is supported by the fact that alpha6beta4 integrin and actin are released from clone A cells by treatment with the F-actin- severing protein gelsolin and that alpha6beta4 immunostaining at the marginal edges of clone A cells on laminin-1 is resistant to solubilization with Triton X-100. Cytokeratins are not observed in filopodia and lamellipodia: alpha6beta4 was extracted from these marginal edges with a Tween-40/deoxycholate buffer that solubilizes the actin cytoskeleton but not cytokeratins. Three other carcinoma cell lines (MIP-101, CCL-228, and MDA-MB-231) exhibit alpha6beta4 colocalized with actin in filopodia and lamellae. Formation of lamellae in these cells is inhibited with an alpha6-specific antibody. Together, these results indicate that the alpha6beta4 integrin functions in carcinoma migration on laminin-1 through its ability to promote the formation and stabilization of actin-containing motility structures (Rabinovitz, 1997).
Wounding of skin activates epidermal cell migration over exposed dermal collagen and fibronectin and
over laminin 5 secreted into the provisional basement membrane. Gap junctional intercellular
communication (GJIC) has been proposed to integrate the individual motile cells into a synchronized
colony. Outgrowths of human keratinocytes in wounds or epibole cultures display parallel
changes in the expression of laminin 5, integrin alpha3beta1, E-cadherin, and the gap junctional protein
connexin 43. Adhesion of keratinocytes on laminin 5, collagen, and fibronectin
differentially regulates GJIC. When keratinocytes are adhered on laminin 5, both structural (assembly
of connexin 43 in gap junctions) and functional (dye transfer) assays show a two- to three-fold
increase compared with collagen and five- to eight-fold over fibronectin. Based on studies with
immobilized integrin antibody and integrin-transfected Chinese hamster ovary cells, the interaction of
integrin alpha3beta1 with laminin 5 is sufficient to promote GJIC. Mapping of intermediate steps in
the pathway linking alpha3beta1-laminin 5 interactions to GJIC indicate that protein trafficking and
Rho signaling are both required. It is suggested that adhesion of epithelial cells to laminin 5 in the
basement membrane via alpha3beta1 promotes GJIC, which integrates individual cells into synchronized
epiboles (Lampe, 1998).
The interactions between tumor cells and laminin or other components of the extracellular matrix have been shown to play an important role in tumor invasion and metastasis. However, the role of the monomeric 67-kDa laminin receptor (67LR) remains unclear. The regulation of 67LR expression was analyzed under different culture conditions with respect to the expression of other well characterized laminin receptors. In A431 cells treated with laminin for different time periods, the regulation of 67LR expression correlates with expression of the alpha6 integrin subunit but not with the expression of other laminin receptors. Moreover, cytokine treatment results in down-modulated expression of the alpha6 integrin subunit and the 67LR. Co-regulation of the expression of the two receptors is further suggested by the observation that specific down-modulation of the alpha6-chain by antisense oligonucleotides is accompanied by a proportional decrease in the cell surface expression of 67LR. Biochemical analyses indicates co-immunoprecipitation of 67LR and the alpha6 subunit with an anti-alpha6 but not an anti-beta1 monoclonal antibody. Co-regulation of 67LR and alpha6 subunit expression, together with the physical association between the two receptors, supports the hypothesis that 67LR is an auxiliary molecule involved in regulating or stabilizing the interaction of laminin with the alpha6beta4 integrin (Ardini, 1997).
The effect of peptide G, a synthetic peptide derived from the sequence of the 37-kDa laminin receptor precursor, on the interaction of laminin was investigated in two tumor cell lines, one of which produces laminin and one of which does not. Addition of peptide G to the culture medium induces a significant increase in the amount of endogenous laminin detectable on the cell membrane of both cell lines. Moreover, pretreatment of exogenous laminin with peptide G dramatically increases laminin binding in both cell lines. Kinetics analysis of membrane-bound labeled laminin reveals a 3-fold decrease in the kd of peptide G-treated laminin compared with either untreated or unrelated or scrambled peptide-treated laminin. Moreover, the affinity constant of peptide G-treated laminin doubles with a doubling of the number of laminin binding sites. Expression of the VLA6 integrin receptor on the cell membrane increases after incubation with peptide G-treated laminin. However, the lower binding inhibition of peptide G-treated laminin after anti-VLA6 antibody or cation chelation treatment indicates that other membrane molecules in addition to integrin receptors are involved in the recognition of peptide G-modified laminin. These "new" laminin-binding proteins also mediate cell adhesion to laminin, the first step in tumor invasion. Together, the data suggest that peptide G increases and stabilizes laminin binding on tumor cells, involving surface receptors that normally do not take part in this interaction. This might explain the abundant clinical and experimental data that suggests a key role for the 67-kDa laminin receptor in the interaction between cancer cells and the basement membrane glycoprotein laminin during tumor invasion and metastasis (Magnifico, 1997).
A laminin-antagonist peptide, comprising amino acids 33-42 of murine epidermal growth factor (mEGF-peptide), interacts with a breast cancer- and endothelial cell-associated YIGSR-specific laminin receptor. This receptor is specific for the laminin B1 chain sequence (Lam.B1-sequence) and is immunologically similar to a 67-kDa laminin receptor. In whole cell receptor assays, mEGF-peptide, Lam.B1-sequence, and laminin all displace laminin from the laminin receptor. Cell attachment to solid-phase laminin is also blocked by all three ligands, but in contrast to the receptor assays, mEGF-peptide or Lam.B1-sequence are less effective than laminin while remaining equipotent with one another. Like laminin, solid-phase mEGF-sequence supports cell attachment; this ability is blocked by anti-67-kDa receptor antibodies. Modeling studies suggest that both peptides present a tyrosyl and an arginyl residue on the same face of a right-handed helical fold with elliptical cross-section (Nelson, 1997).
Dystroglycan (see Drosophila Dystroglycan) was originally identified as an extracellular and transmembrane constituent of a large oligomeric complex of sarcolemmal proteins associated with dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene. During the last few years, dystroglycan has been demonstrated to be a novel receptor of not only laminin but also agrin, two major proteins of the extracellular matrix producing distinct biological effects. The fact that the drastic reduction of dystroglycan in the sarcolemma, caused by the absence of dystrophin, leads to muscle cell death in DMD patients and mdx mice indicates that, as a laminin receptor, dystroglycan contributes to sarcolemmal stabilization during the contraction and stretching of striated muscle cells. Dystroglycan is also expressed in the neuromuscular junction and non-muscle tissues such as kidney, brain and peripheral nerve, and, as a receptor of laminin/agrin, has been implicated in such diverse and specific developmental processes as epithelial morphogenesis, synaptogenesis and myelinogenesis. These findings point to the fundamental role of dystroglycan in the cellular differentiation process shared by many different cell types. This paper reviews the recent publications on the biological functions of dystroglycan and discusses its roles in cell differentiation (Matsumura, 1997).
The transition of laminin from a monomeric to a polymerized state is thought to be a crucial step in the development of basement membranes and in the case of skeletal muscle, mutations in laminin can result in severe muscular dystrophies with basement membrane defects. Laminin polymer and receptor interactions have been evaluated to determine the requirements for laminin assembly on a cell surface and what cellular responses might be mediated by this transition have been investigated. In muscle cell surfaces, laminins preferentially polymerize while bound to receptors that included dystroglycan and alpha7beta1 integrin. These receptor interactions are mediated through laminin COOH-terminal domains that are spatially and functionally distinct from NH2-terminal polymer binding sites. This receptor-facilitated self-assembly drives rearrangement of laminin into a cell-associated polygonal network, a process that also requires actin reorganization and tyrosine phosphorylation. As a result, dystroglycan and integrin redistribute into a reciprocal network as do cortical cytoskeleton components vinculin and dystrophin. Cytoskeletal and receptor reorganization is dependent on laminin polymerization and fails in response to receptor occupancy alone (nonpolymerizing laminin). Preferential polymerization of laminin on cell surfaces, and the resulting induction of cortical architecture, is a cooperative process requiring laminin-receptor ligation, receptor-facilitated self-assembly, actin reorganization, and signaling events (Colognato, 1999).
Dystroglycan is a receptor for the basement membrane components laminin-1, -2, perlecan, and agrin. Genetic studies have revealed a role for dystroglycan in basement membrane formation of the early embryo. Dystroglycan binding to the E3 fragment of laminin-1 is involved in kidney epithelial cell development, as revealed by antibody perturbation experiments. E3 is the most distal part of the carboxyterminus of laminin alpha1 chain, and is composed of two laminin globular (LG) domains (LG4 and LG5). Dystroglycan-E3 interactions are mediated solely by discrete domains within LG4. The role of this interaction has been examined in the development of mouse embryonic salivary gland and lung. Dystroglycan mRNA is expressed in epithelium of developing salivary gland and lung. Immunofluorescence has demonstrated dystroglycan on the basal side of epithelial cells in these tissues. Antibodies against dystroglycan that block binding of alpha-dystroglycan to laminin-1 perturb epithelial branching morphogenesis in salivary gland and lung organ cultures. Inhibition of branching morphogenesis is seen in cultures treated with polyclonal anti-E3 antibodies. One monoclonal antibody (mAb 200) against LG4 blocks interactions between a-dystroglycan and recombinant laminin alpha1LG4-5, and also inhibits salivary gland and lung branching morphogenesis. Three other mAbs, also specific for the alpha1 carboxyterminus and known not to block branching morphogenesis, fail to block binding of alpha-dystroglycan to recombinant laminin alpha1LG4-5. These findings clarify why mAbs against the carboxyterminus of laminin alpha1 differ in their capacity to block epithelial morphogenesis and suggest that dystroglycan binding to alpha1LG4 is important for epithelial morphogenesis of several organs (Durbeej, 2001).
Dystroglycan (DG) function is required for the formation of basement membranes in early development and the organization of laminin on the cell surface. DG-mediated laminin clustering on mouse embryonic stem (ES) cells is a dynamic process in which clusters are consolidated over time into increasingly more complex structures. Utilizing various null-mutant ES cell lines, roles for other molecules in this process have been defined. In beta1 integrin-deficient ES cells, laminin-1 binds to the cell surface, but fails to organize into more morphologically complex structures. This result indicates that beta1 integrin function is required after DG function in the cell surface-mediated laminin assembly process. In perlecan-deficient ES cells, the formation of complex laminin-1 structures is defective, implicating perlecan in the laminin matrix assembly process. Moreover, laminin and perlecan reciprocally modulate the organization of the other on the cell surface. Taken together, the data support a model whereby DG serves as a receptor essential for the initial binding of laminin on the cell surface, whereas beta1 integrins and perlecan are required for laminin matrix assembly processes after it binds to the cell (Henry, 2001).
The C-terminal G domain of the mouse laminin alpha2 chain consists of five lamin-type G domain (LG) modules (alpha2LG1 to alpha2LG5) and was obtained as several recombinant fragments, corresponding to either individual modules or the tandem arrays alpha2LG1-3 and alpha2LG4-5. These fragments were compared with similar modules from the laminin alpha1 chain and from the C-terminal region of perlecan (PGV) in several binding studies. Major heparin-binding sites were located on the two tandem fragments and the individual alpha2LG1, alpha2LG3 and alpha2LG5 modules. The binding epitope on alpha2LG5 could be localized to a cluster of lysines by site-directed mutagenesis. In the alpha1 chain, however, strong heparin binding was found on alpha1LG4 and not on alpha1LG5. Binding to sulfatides correlated to heparin binding in most but not all cases. Fragments alpha2LG1-3 and alpha2LG4-5 also bound to fibulin-1, fibulin-2 and nidogen-2 with Kd = 13-150 nM. Both tandem fragments, but not the individual modules, bound strongly to alpha-dystroglycan and this interaction was abolished by EDTA but not by high concentrations of heparin and NaCl. The binding of perlecan fragment PGV to alpha-dystroglycan was even stronger and was also not sensitive to heparin. This demonstrated similar binding repertoires for the LG modules of three basement membrane proteins involved in cell-matrix interactions and supramolecular assembly (Talts, 1999).
Developmental abnormalities of myelination are observed in the brains of laminin-deficient humans and mice. The mechanisms by which these defects occur remain unknown. It has been proposed that, given their central role in mediating extracellular matrix (ECM) interactions, integrin receptors are likely to be involved. However, it is a non-integrin ECM receptor, dystroglycan, that provides the key linkage between the dystrophin-glycoprotein complex (DGC) and laminin in skeletal muscle basal lamina, such that disruption of this bridge results in muscular dystrophy. In addition, the loss of dystroglycan from Schwann cells causes myelin instability and disorganization of the nodes of Ranvier. To date, it is unknown whether dystroglycan plays a role during central nervous system (CNS) myelination. This study reports that the myelinating glia of the CNS, oligodendrocytes, express and use dystroglycan receptors to regulate myelin formation. In the absence of normal dystroglycan expression, primary oligodendrocytes showed substantial deficits in their ability to differentiate and to produce normal levels of myelin-specific proteins. After blocking the function of dystroglycan receptors, oligodendrocytes failed both to produce complex myelin membrane sheets and to initiate myelinating segments when co-cultured with dorsal root ganglion neurons. By contrast, enhanced oligodendrocyte survival in response to the ECM, in conjunction with growth factors, was dependent on interactions with beta-1 integrins and did not require dystroglycan. Together, these results indicate that laminins are likely to regulate CNS myelination by interacting with both integrin receptors and dystroglycan receptors, and that oligodendrocyte dystroglycan receptors may have a specific role in regulating terminal stages of myelination, such as myelin membrane production, growth, or stability (Colognato, 2007).
Laminin-5 is a heterotrimeric molecule with three chains: a 100-kDa alpha3 chain, a 140-kDa beta3 chain and a 155-kDa gamma2 chain, all three products of different genes. Both integrins alpha6/beta4 and alpha3/beta1 are known to bind to laminin-5. The alpha3/beta1 receptor may be involved in the initial attachment of keratinocytes to laminin-5. Laminin-5 (previously known as kalinin, epiligrin, and nicein) is an adhesive protein localized to the anchoring filaments within the lamina lucida space of the basement membrane zone lying between the epidermis and dermis of human skin. Anchoring filaments are structures within the lamina lucida and lie immediately beneath the hemidesmosomes of the overlying basal keratinocytes apposed to the basement membrane zone. Human keratinocytes synthesize and deposit laminin-5. Laminin-5 is present at the wound edge during reepithelialization. Laminin-5, a powerful matrix attachment factor for keratinocytes, inhibits human keratinocyte migration. The inhibitory effect of laminin-5 on keratinocyte motility can be reversed by blocking the alpha3 integrin receptor. Laminin-5 inhibits keratinocyte motility driven by a collagen matrix in a concentration-dependent fashion. Using antisense oligonucleotides to the alpha3 chain of laminin-5 and an antibody that inhibits the cell binding function of secreted laminin-5, it has been demonstrated that the endogenous laminin-5 secreted by the keratinocyte also inhibits the keratinocyte's own migration on matrix. These findings explain the hypermotility that characterizes keratinocytes from patients who have forms of junctional epidermolysis bullosa associated with defects in one of the genes encoding for laminin-5 chains, resulting in low expression and/or functional inadequacy of laminin-5 in these patients. These studies also suggest that during reepithelialization of human skin wounds, the secreted laminin-5 stabilizes the migrating keratinocyte to establish the new basement membrane zone (O'Toole, 1997).
Continued: see Laminin A Evolutionary homologs part 3/3 | Return: part 1/3
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