Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Laminin β2

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101519

Synonyms

Historical Background

Laminin β2 was identified as basement membrane a component in neuromuscular junctions (NMJs). Basement membranes are thin sheet-like structures that abut many cell types, including epithelial, endothelial, fat, muscle, and peripheral nerve cells. They influence tissue compartmentalization and cellular phenotypes during developmental and regenerative processes. Although a pure basement membrane was necessary to investigate its composition, it was difficult to purify the basement membrane from various tissues, including NMJs. The Matrigel matrix, an extract derived from mouse Engelbreth-Holm-Swarm sarcoma, is composed of type IV collagen, laminin, nidogen, and perlecan, which are the major components of basement membranes. Therefore, the Matrigel matrix has been used as a reconstituted basement membrane. Although Matrigel has significantly advanced many studies of basement membranes, several reports have suggested that the basement membrane in NMJs is more specific than that in other tissues. To characterize the molecules of the synaptic basement membrane, Sanes et al. adopted an immunohistochemical approach (Sanes et al. 1990). A specific molecule, laminin β2, was initially defined by an antiserum to an alkali digest of bovine lens capsule that is a portion of the basement membrane. The antiserum, named JS-1, recognized synaptic basement membrane rather than the extrasynaptic membrane in adult rat muscle (Sanes and Hall 1979). Additional monoclonal antibodies, C4, D5, and D7, were generated against the same antigen. The cDNAs encoding the recombinant proteins reactive to these monoclonal antibodies were isolated from a rat kidney-derived library. Analysis of these cDNA sequences revealed homologies with laminin subunits. Therefore, the specific antigen in NMJs was initially named s-laminin. After the first revision of laminin nomenclature (Burgeson et al. 1994), s-laminin was renamed laminin β2, and the gene was named LAMB2.

Structure and Function of Laminin β2

Laminins are heterotrimers consisting of one α, one β, and one γ chain and are the predominant components of basement membranes (Durbeej 2010). As shown in Fig. 1a, the typical shape of laminin heterotrimers is a cruciform configuration. Five α, three β, and three γ chains derived from distinct genes have been described in vertebrates (Fig. 1b). All laminin heterotrimers are named according to their α, β, and γ chain composition (Aumailley et al. 2005). For instance, laminin-521 (LM-521) is composed of α5, β2, and γ1 chains (Fig. 1a). In all chains, laminin coiled-coil (LCC) domains mediate heterotrimer assembly and form a long arm with laminin globular (LG) domains. All five laminin α chains have LG domains at their C-terminus, which consists of five homologous domains (LG1–LG5). Cell adhesion to laminins is mediated by the binding of various receptors, including integrin and nonintegrin receptors that mainly bind to the LG domains. Although several reports have shown that β and γ chains also have cell adhesion activities, they do not seem to be the major cell attachment sites. The short arms are composed of the globular laminin N-terminal domain (LN) and globular laminin 4 (L4) or globular laminin four (LF) domains separated by rod-like elements with laminin epidermal-growth-factor-like motifs (LE). All laminin chains have signal sequences for secretion, and the laminin heterotrimers are assembled in the endoplasmic reticulum and secreted into extracellular spaces. LN domains are present in the short arms of α1, α2, α3B, α5, β1, β2, β3, γ1, and γ3 chains and are essential for self-matrix-assembly and/or incorporation into basement membranes. Truncated short arms are observed in the α3A, α4, β3, and γ2 chains. The laminin heterotrimers with truncated short arm chain(s), the Y-shaped and rod-shaped forms, bind to the other extracellular matrix components, and the complexes are integrated into basement membranes. Laminin γ1 also binds to nidogens at its nidogens with one of its LE motifs (γ1LEb3). This interaction is considered essential for basement membrane assembly. Laminin β chains have a laminin β-knob domain (Lβ) inserted in the LCC domain. The Lβ domain is a major characteristic that distinguishes β chains from the other chains.
Laminin β2, Fig. 1

Structure of the laminin trimer and subunits. (a) Laminin-521 (LM-521) is shown as a representative of β2 chain-containing laminin structure. All laminins, including LM-521, have one α, one β, and one γ chain that form a trimer using the coiled-coil domains. LN laminin N-terminal domain, LE laminin epidermal-growth-factor like domain, L4 laminin 4 domain, LF laminin four domain, LCC laminin coiled-coil domain, LG laminin globular domain, laminin β-knob domain, hinge nonglobular link between LG3 and LG4. (b) Laminin chains. The C-terminal globular domain of the α chain is composed of a tandem array of five modules and mediates receptor binding. The color-coding of each chain is used in Figs. 2, 3b, and 4b

Laminin β2 cDNAs were initially cloned from the rat kidney library (Hunter et al. 1989b). The predicted amino acid sequence was homologous to mouse and human laminin β1 sequences. In humans, the amino acid sequence of laminin β2 shows 50% sequence identity to the β1 chain and 36.3% to the β3 chain (Wewer et al. 1994). The domain structure of laminin β2 is more similar to the β1 chain than to the β3 chain. The short arm of the laminin β2 chain contains two globular domains (LN and LF) and two rod-like elements (LEa and LEb), similar to laminin β1. The length of the laminin β2 LCC domain containing Lβ domain is similar to that of the other laminin LCC domains, which indicates that the β2 chain can assemble with all α and γ chains. To date, 19 different laminin isoforms have been identified in various cultured cells and tissues (Durbeej 2010). Of them, nine isoforms contain laminin β2 (Fig. 2) and adopt a cruciform or truncated shape. Of the truncated laminins, LM-3A21, LM-421, and LM-423 are Y-shaped. LM-521 is the most studied isoform.
Laminin β2, Fig. 2

Schematic diagrams of laminin heterotrimer structures containing β2 chains. LM-121, LM-221, LM-521, and LM-523 have classic cruciform structure. They have three LN domains, allowing them to polymerize into a network via inter-trimer LN domain interaction. LM-222, LM-3A21, LM-421, LM-423, and LM-522 contain truncated chains and are unable to self-polymerize

Laminins are major cell-adhesive proteins that are capable of binding to integrins. Integrins are heterodimeric membrane proteins that are composed of noncovalently associated α and β subunits. To date, 24 integrins have been identified in mammals (Humphries et al. 2006). Of these integrins, integrins α3β1, α6β1, α6β4, and α7β1 have been identified as the major laminin receptors in various cell types (Durbeej, 2010). The α7X1 and α7X2 subunits, which contain alternatively spliced X1 or X2 regions in the extracellular β-propeller domain, add diversity to the α7β1 integrin. Of integrins binding to laminins, integrin α3β1 is classified as an X2-type integrin. The α3β1 and α7X2β1 integrins are capable of distinguishing between β1- and β2-containing laminins (Taniguchi et al. 2009). The C-terminal 20 amino acid sequence of the laminin β2 chain modulates the binding affinities of laminins to X2-type integrins. Because β2-containing laminins and X2-type integrins colocalize in several tissues, the high affinity interactions between them may contribute to the functions that are not compensated by the laminin β1 chain.

Expression and Distribution of Laminin β2

Initially, laminin β2 was considered to have a restricted distribution pattern based on the selective staining of NMJs in skeletal muscle and glomerulus in kidney by specific anti-laminin β2 antibodies (Hunter et al. 1989b). Thereafter, several groups revealed that the β2 chain dominates at sites such as the synaptic cleft of NMJs, the glomerular basement membrane (GBM), and the basement membrane of the retina, although β1 and β2 chains are ubiquitously expressed in various tissues (Hunter et al. 1992; Iivanainen et al. 1995; Miner et al. 1997; Patton et al. 1997; Sasaki et al. 2002). The distribution patterns of β2-containing laminins are further restricted by the expression of α and γ chains (Fig. 2) (Durbeej 2010).

In skeletal muscles, the basement membrane ensheathes each muscle fiber and occupies the NMJ synaptic cleft between axon terminals and muscles. The basement membrane of muscle fiber also continues to the basement membrane of Schwann cells wrapping around axons. In the early stage of mouse embryogenesis, laminin α2, α4, α5, β1, and γ1 chains are present in both the extrasynaptic and synaptic regions, whereas the β2 chain is restricted to the synaptic basement membrane from its first appearance (Patton et al. 1997). In the late embryogenesis stage, the distribution pattern of the α2 chain remains broad, whereas the expression of α4 and α5 chains in the extrasynaptic basement membrane decreases markedly, and the β1 chain is lost from the synaptic basement membrane. In adults, laminin α4 is restricted to primary synaptic clefts of NMJs, whereas laminin α5 is present in primary synaptic clefts and junctional folds. Therefore, LM-211 is present in adult extrasynaptic basement membrane, and the synaptic basement membrane contains LM-221, LM-421, and LM-521 (Fig. 3a).
Laminin β2, Fig. 3

LM-221, LM-421, and LM-521 in NMJs. (a) Distribution pattern of laminins in NMJs. Laminins containing the β2 chain are specifically localized in the synaptic cleft, the space between axon and muscle fiber. (b) Diagram of the synaptic cleft between the presynaptic and postsynaptic membranes. The electron dense material of active zones is shown in light brown. Laminin β2 binds to voltage-gated calcium channels (VGCCs) and organizes the active zones. AChR acetylcholine receptor

In adult peripheral nerves, myelinated axons and fascicles of myelinated axons are surrounded by endoneurial and perineural basement membranes, respectively. LM-421 and LM-521, which contains the β2 chain, are present in perineural basement membranes, and endoneurial basement membranes contain LM-211(Patton et al. 1998). The endoneurial basement membrane that is close to NMJs contains LM-411. As described above, laminin β2 is concentrated in the synaptic basement membrane. An in vitro study showed that the C-terminus of the β2 chain is necessary for the synaptic localization of laminin β2 (Martin et al. 1995).

Consistent with the distribution pattern of laminin β2 in NMJs of skeletal muscles and in GBMs of kidney, mice lacking laminin β2 (Lamb2−/−) exhibit developmental defects in neuromuscular synapse formation and glomerular filtration (Noakes et al. 1995a; Noakes et al. 1995b). Therefore, Lamb2−/− mice die between postnatal days 15 and 30. The mutant mice also exhibit defective rod photoreceptor synapses due to the aberrant elongation of the outer segment (Libby et al. 1999). Genetic deletion of laminin β2 and γ3 disrupts the development of the basement membrane of the retina, i.e., the inner limiting membrane, which maintains the apical-basal polarity of Müller cells, astrocyte migration, and vascular integrity (Gnanaguru et al. 2013; Pinzon-Duarte et al. 2010). Thus, deletion of laminin β2 causes defects in NMJs, kidney, and retina.

Roles of Laminin β2 in NMJs

Synaptic transmission at NMJs directs the contraction or relaxation of skeletal muscle. An NMJ is a chemical synapse that is formed between a motor neuron and a muscle fiber (Fig. 3a). At NMJs, an axon terminal occupies a depression of the muscle fiber and forms a synaptic cleft with junctional folds, which are filled with basement membrane containing laminin β2. The axon terminal contains mitochondria and synaptic vesicles filled with the neurotransmitter acetylcholine. The neurotransmitter is released at active zones, which are protein-dense areas of the presynaptic plasma membrane. The neurotransmitter release is initiated by the calcium ion influx through voltage-gated calcium channels (VGCCs). The released acetylcholine binds to acetylcholine receptors (AChRs) at crests of the junctional folds of the muscle plasma membrane to accomplish synaptic transmission.

The roles of laminin β2 in NMJs are exemplified in the defective NMJs of Lamb2−/− mice (Noakes et al. 1995a). In the Lamb2 mutant mice, active zones disappear and synaptic vesicles are not concentrated at nerve terminals that abut muscle fibers. In search for laminin β2 specific receptors, β2 chain of LM-421 and LM-521 were identified as ligands that bind to the eleventh extracellular domain of N- and P/Q-type VGCCs (Fig. 3b) (Nishimune et al. 2004). These VGCCs are concentrated in presynaptic terminals at NMJs and are required for neurotransmitter release from motor nerve terminals. However, LM-521 does not bind to R- and L-type VGCCs, which are not concentrated at NMJs. Interestingly, laminin β2-containing synaptic laminins bind to P/Q-type VGCCs, but β1 chain-containing nonsynaptic laminins (LM-111) do not bind to any of these VGCCs. These results suggest that synaptic laminins containing laminin β2 bind specifically to VGCCs concentrated at NMJ presynaptic terminals. In addition, P/Q-type VGCCs distinguish laminins containing laminin β2 from those without laminin β2. Importantly, the number of active zones decreases significantly when the interaction between laminin β2 and P/Q-type VGCCs is inhibited acutely in wild-type mice in vivo (Nishimune et al. 2004). Consistently, double knockout mice lacking N- and P/Q-type VGCCs exhibit a decreased number of active zones in otherwise normally formed NMJs (Chen et al. 2011a). The active zone loss phenotype identified in these in vivo experiments does not seem to be a secondary phenotype to NMJ degeneration. These results suggest that the interaction between synaptic laminins with laminin β2 and presynaptic VGCCs organizes active zones at NMJs.

Hunter et al. showed that chick ciliary neurons (parasympathetic neurons innervating ocular muscles) adhere to a preparation containing laminin β2 chain (Hunter et al. 1989b). They further identified a primary sequence in the C-terminus of the β2 chain that is involved in the adhesion of motor neurons (Hunter et al. 1989a). Recombinant proteins and synthetic peptides containing the identified LRE (Leucine-Arginine-Glutamate) sequence exhibit adhesive activities for ciliary neurons (Hunter et al. 1991). The LRE-containing C-terminal 20 kDa region of laminin β2 is also necessary and sufficient for laminin interactions with VGCCs (Nishimune et al. 2004). The VGCC is a candidate receptor that mediates the adhesion of motor neurons to laminin β2. The 100 amino acid sequence surrounding the LRE sequence is very well conserved among human, mice, and rats; however, the LRE motif is not conserved in the human β2 chain. The human laminin β2 chain contains a tripeptide LRG (Leucine-Arginine-Glycine) sequence in the corresponding region. It has not been tested whether the LRG sequence has adhesive activity for neurons and/or binds to VGCCs.

In Lamb2−/− mice, Schwann cells intrude into the synaptic cleft, the junctional folds are lost, and nerve terminals detach from muscle fibers (Noakes et al. 1995a). An in vitro study showed that LM-521, but not LM-221, inhibits process extension of Schwann cells (Patton et al. 1998). The LRE sequence of laminin β2 is not necessary for the Schwann cell repellent effect. These results suggest that Schwann cells use a receptor different from the neuronal receptors recognizing the LRE sequence in laminin β2. Furthermore, this receptor is likely to recognize a combination of laminin α5, β2, and γ1 chains, not just the β2 chain, as VGCCs do. The receptor that repels Schwann cells from the NMJ synaptic cleft has not yet been identified.

In addition to the active zone and Schwann cell phenotypes, Lamb2−/− mice exhibit neurotransmission impairment at NMJs (Knight et al. 2003; Noakes et al. 1995a). The miniature endplate potential frequency and the mean quantal content are both significantly decreased in Lamb2−/− NMJs compared to control NMJs. Interestingly, Lamb2 mutant NMJs also exhibit a failure to switch from N- and P/Q-type VGCC-mediated synaptic transmission during development to P/Q-type VGCC dependent transmission at mature NMJs (Chand et al. 2015). These physiological phenotypes are consistent with the aforementioned active zone loss phenotype that was identified in Lamb2−/− mice because a loss of active zones is equal to a loss of synaptic vesicle release sites. Furthermore, these symptoms in Lamb2−/− mice are consistent with the symptoms of patients with Pierson syndrome with Lamb2 gene mutations who show neuromuscular defects, renal failure, and severe ocular abnormalities (Matejas et al. 2010).

Roles of Laminin β2 in Glomerulus

In kidney, basement membranes serve as both structural barriers for tubular epithelia and components of the glomerular filter (Fig. 4a). There are transitions in the isoforms of basement membrane components that are deposited in the developing GBM (Miner, 2011). During glomerulogenesis, the transition of laminin isoforms is especially drastic (Miner et al. 1997). The nascent GBM initially contains LM-111 and LM-411, and LM-511 is incorporated at the S-shape stage. By the capillary loop stage, LM-111 is eliminated from the GBM, and LM-421 and LM-521 begin to accumulate. In mature glomerulus, only components of the β2-containing LM-521 are detected in the GBM (Miner 2011). The GBM is derived from the fusion of the basement membranes of podocytes and endothelial cells and is composed of lamina rara and densa (Fig. 4b). Endothelial cells on the GBM bear many fenestrations that allow efficient flow across the glomerular filter. Podocytes enwrap the outer aspect of glomerular capillaries with foot processes containing filtration slits. Consistent with the dominant deposition of the β2 chain in GBMs, laminin β2 mutant mice exhibit heavy proteinuria due to nephrotic syndrome with podocyte foot process effacement (Noakes et al. 1995b). The deletion of laminin β2 in GBMs also causes the mislocalization of anionic sites that modulate the permeability of plasma proteins, such as albumin (Jarad et al. 2006).
Laminin β2, Fig. 4

LM-521 in GBM. (a) Distribution of laminins in mature glomerulus. Although immature GBMs possess the β1 chain, a transition from β1 to β2 occurs during maturation. Therefore, LM-521 containing β2 chain is solely deposited in mature GBM. (b) Podocytes and endothelial cells on GBMs. Laminin β2 is essential for the formation of podocyte foot processes and localization of anionic sites. Arrowheads indicate fenestrations, and two-way arrows indicate filtration slits. The color codes for laminin subunits in Fig. 4b are the same as Fig. 1

Pierson syndrome is caused by autosomal recessive mutations in the laminin β2 gene (LAMB2) and is characterized by renal failure, severe ocular abnormalities, and neuromuscular defects (Matejas et al. 2010). The human laminin β2 gene has 32 exons that span 12 kbp of genomic DNA (Fig. 5a). The truncating mutations are distributed across the entire gene, and most mutations eliminate the laminin β2 function completely. Occasionally, Pierson syndrome is associated with milder or oligosymptomatic disease variants. One of the missense mutations, R246W, leads to a significant reduction in protein expression and exhibits less severe extrarenal defects (Zenker et al. 2004). The missense mutations are clearly clustered in the LN domain, which is required for the polymerization of laminins (Fig. 5b). Therefore, mutations in the LN domain possibly perturb the formation of the basement membrane. Human and mouse β2 genes have nearly identical exon-intron organization, and amino acids at several mutation sites are conserved among human and mouse genes. Therefore, Lamb2−/− mice expressing mutated β2 chains have been used as models of Pierson syndrome. A mouse model expressing laminin β2 with a R246Q mutation exhibits less severe proteinuria compared to Lamb2−/− mice (Chen et al. 2011b). The level of proteinuria correlates inversely with the level of R246Q expression. An in vitro study showed that the R246Q mutation results in the impaired secretion of LM-521. These results suggest that the R246Q mutation causes nephrotic syndrome by impairing the secretion of LM-521; however, high expression of the mutant protein can overcome the defect by secreting a sufficient amount of laminins and ameliorating proteinuria. Another missense mutation, C321R, leads to congenital nephrotic syndrome with mild extrarenal symptoms (Matejas et al. 2010). This mutation affects one of the conserved cysteines in the first EGF-like module, LEa1 (Fig. 5c). The cysteine residues form disulfide bonds that stabilize the structure of the EGF-like module. The C321R mutation causes the defective secretion of LM-521 from podocytes to the GBM, accompanied by podocyte endoplasmic reticulum stress (Chen et al. 2013). Thus, mechanisms to upregulate laminin β2 secretion may be a therapeutic target for Pierson syndrome. Importantly, the forced expression of the β1 chain rescues defects of Lamb2−/− mice because the β1 and β2 chains are structurally similar (Suh et al. 2011). Therefore, effective substitution of the β2 chain by the β1 chain in the GBM may be a potential therapeutic approach for ameliorating the glomerular filtration defect in Pierson syndrome.
Laminin β2, Fig. 5

Mutation in the human LAMB2 gene. (a) Genomic structure of the human LAMB2 gene. Vertical bars and horizontal lines represent exons and introns, respectively. Numerals indicate exon numbers. Untranslated regions are shown as hatched boxes. White and gray boxes encode globular domains and tandems of EGF-like modules, respectively. Light gray boxes encode LCC and Lβ domains. Truncating mutations are indicated by black arrows. Arrowheads indicate splice site mutations. Missense mutations and in frame deletions are indicated by red arrows. (b) Domain structure of laminin β2. Asterisks indicate positions of missense mutation in LN, LEa, and LCC domains. Missense and deletion mutations are mostly located in the LN domain. (c) Structure of the first EGF-like module (LEa1) with letters corresponding to the one letter amino acid code. The cysteine residues connected with solid lines indicate disulfide bonds. The missense mutation C321R loses one of the conserved cysteines in the EGF-like module. The dotted lines indicate putative disulfide bonds. The mutation results in protein misfolding that leads to ER stress

Biomaterials

Laminins have been used as culture substrata for stem cells. Long-term self-renewal of human pluripotent stem cells in defined culture systems needs to be achieved without mouse feeder cells. LM-521, but not LM-511, enables clonal culturing of human embryonic stem cells under defined and xeno-free conditions (Rodin et al. 2014). However, the advantage reason of the β2 chain remains unclear.

The development of biomimetic materials is a focus in the field of tissue engineering. Biologically active sequences derived from laminins and other extracellular matrices have been used to design biomimetic materials (Rahmany and Van Dyke 2013). The LRE sequence of the β2 chain may be a useful material for modulating the direction of neurite extension.

Summary

Laminin β2 was originally identified as a specific antigen in NMJs. It is a subunit of laminin chains and assembles with α and γ chains. Laminin heterotrimers are a family of glycoproteins that are major components of the basement membrane, in which they play structural and functional roles. Laminin β2 has unique expression patterns and restricted localization in basement membranes. It is preferentially found in the NMJ synaptic cleft in skeletal muscles, the GBM of kidney, and the inner limiting membrane of the retina. Consistent with the distribution pattern, mice lacking laminin β2 exhibit defects in neuromuscular and retinal synapse development and glomerular filtration. The defects of Lamb2−/− mice correspond to the clinical manifestations of Pierson syndrome, which is caused by mutations of the LAMB2 gene that encodes laminin β2. Forced expression of laminin β2 with Pierson syndrome mutations in Lamb2−/− mice ameliorates the severe nephrosis and neuromuscular abnormalities identified in Lamb2−/− mice. Upregulation of laminin β2 in GBM and NMJs is a potential therapeutic target in Pierson syndrome.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Clinical BiochemistryTokyo University of Pharmacy and Life SciencesTokyoJapan
  2. 2.Department of Anatomy and Cell BiologyUniversity of Kansas, School of MedicineKansas CityUSA