Laminin where is it found

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Correspondence to Jeffrey A. Provisional Patent application no. The remaining authors declare no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions. Ishihara, J. Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing. Nat Commun 9, Download citation. Received : 24 July Accepted : 01 May Published : 04 June Anyone you share the following link with will be able to read this content:.

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Advanced search. Skip to main content Thank you for visiting nature. Download PDF. Subjects Diabetes complications Extracellular matrix Regenerative medicine. Abstract Laminin, as a key component of the basement membrane extracellular matrix ECM , regulates tissue morphogenesis.

Introduction Laminins are the most abundant glycoproteins of the basement membrane extracellular matrix ECM and can be found in almost all tissues of the body. Full size image.

Discussion As a cell scaffold protein, laminin tightly regulates cell adhesion, motility, survival, and differentiation, thus playing a critical role in tissue homeostasis and wound healing 8. Release of GF from fibrin matrix Fibrin matrices were generated with human fibrinogen von Willebrand factor and fibronectin depleted, Enzyme Research Laboratories as described previously Statistical analysis Statistical methods were not used to predetermine the necessary sample size, but sample sizes were chosen based on estimates from pilot experiments and previously published results such that appropriate statistical tests could yield significant results.

Data availability The data that support the findings of this study are available from the authors upon reasonable request. References 1. Article Google Scholar 4. PubMed Google Scholar Article Google Scholar This conclusion isseemingly in disagreement with the Henry and Campbell article.

In that analysis, it was reported that basement membranes failed to form in dystroglycan-null EBs, and it was therefore suggested that dystroglycan is essential for basement membrane assembly.

However, this could not represent a general receptor requirement as was implied because knockout of the dystroglycan gene in mice is characterized by a loss of Reichert's membrane, but not a loss of the embryonal basement membrane adjacent to epiblast Williamson et al. Furthermore, the skeletal muscle of dystroglycan-deficient chimeric mice has been found to possess basement membrane Cote et al.

Together, we conclude that dystroglycan is not a fundamental requirement for basement membrane assembly in tissues. A striking finding in our analysis was the loss of the epiblast layer through apoptosis. It has previously been observed that only those cells that adhere to basement membrane survive to differentiate with the nonadherent cells undergoing anoikis Coucouvanis and Martin, However, continued survival of the epiblast was clearly dependent upon a dystroglycan interaction.

This receptor dependency was significantly greater than that which we observed in the laminin-rescued integrin null, and a general survival role for dystroglycan is supported by in vitro studies conducted on muscle cells Montanaro et al. The survival deficit seen in both receptor nulls raises the possibility that cell adhesion strength determines survival regardless of the specific receptor involved, and that the observed difference in survivability is due to asymmetric compensation in which only the integrin-null loss of receptor binding is largely replaced by high cell surface expression of dystroglycan.

In each case, assembly and differentiation could be rescued with exogenous laminin-1, strongly suggesting that lack of extracellular laminin, rather than a problem with cell surface ability to mediate assembly, caused the defect. During development, laminin expression became restricted to the zone underneath the endodermal layer, the major source of laminin synthesis and secretion Murray and Edgar, a. Interestingly, the findings of Li et al.

Our data provide evidence for a mechanism in which laminin must both polymerize through its LN domains Yurchenco and Cheng, and interact with the cells of the ICM through a heparin-binding sequence in LG4 to initiate site-specific basement membrane assembly and to trigger differentiation.

The new findings also argue that the laminin polymer creates the initial architectural scaffolding that must assemble before other components can accumulate into the ECM, and that is crucial for cellular differentiation. Wild-type R1 Smyth et al. ES cells were subcultured at semi-confluence, and the medium was changed every day to maintain the cells in an undifferentiated state.

To culture EBs, subconfluent ES cells were dispersed with 0. EBs were collected into ml tubes and allowed to sediment by gravity. After washing in PBS with 0. The cell pellet was fixed in 0. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end-labeling Promega.

DNA fragments were end-labeled with 0. Protein in solution was determined either by absorbance at nm or the Bradford assay Bio-Rad Laboratories. After collagenase digestion, the immunoprecipitates were washed twice in PBS and analyzed. Laminin domains contributing to basement membrane assembly. C Quantitation of degree of basement membrane formation. Expression of differentiation markers.

HPRT was used as normalizing control. Basement membranes assemble in dystroglycan-null EBs. Dystroglycan-null ES cells, suspended at the first passage from feeder cell layers, were allowed to form EBs for 5 d in the absence of any treatment.

A Phase micrograph and B methylene blue—stained section show epiblast differentiation, cavitation, and thin basement membranelike structures arrows. Development of epiblast apoptosis and basement membrane thickening in dystroglycan-null EBs. Untreated dystroglycan-null EBs and wild-type controls were cultured for 5—9 d. An epiblast layer is seen in both forms of EBs. By 9 d, epiblast layer degeneration is observed. Epiblast apoptosis was prominent in the dystroglycan-null, but not the wild-type, EBs, and was augmented over time.

The EBs with partial and complete degeneration and loss of the epiblast layer were subtracted from the total EBs counted. The plot shows the percentage of remaining EBs with surviving epiblast layers. Ultrastructure of EBs. The regions containing junctions of the endodermal layer and ICM or epiblast layer are shown.

Endoderm above arrows was present; however, neither basement membrane nor epiblast differentiation is present. B Wild-type embryoid body 7 d reveals basement membrane between endoderm and epiblast between arrows. Basement membrane arrows is located between endoderm and epiblast layers. Scattered small clefts arrowhead located between cell and matrix were present more frequently in these EBs compared with wild-type.

Endodermal differentiation in the absence of basement membrane was seen. No basement membrane or epiblast differentiation was detected. Note prominent basement membrane between endoderm and epiblast layers arrows. H and I Dystroglycan-null EBs, 5 d. Note typical basement membrane H lying between endoderm and epiblast cell layers. The RER asterisk of the endoderm is dilated.

Dystroglycan distribution and expression. Inset shows heavier sample load for wild-type and dystroglycan-null EBs. Expression and accumulation of basement membrane components. The cell pellets were extracted with 0. Alternatively, the extract or medium fraction was analyzed directly with EHS lamininspecific pAb in immunoblots IB.

A Laminin. B Nidogen. Type IV collagen immunoprecipitated from wild-type conditioned medium or EBs could be digested with bacterial collagenase lane 5. Model of laminin interactions. Laminin polymerizes through its short arms creating a multivalent network. The ICM, requiring this network, but not requiring integrin or dystroglycan, becomes polarized and converted to epiblast. Type IV collagen forms a second network and nidogen and perlecan are incorporated into a more stable ECM.

Mesodermal differentiation is delayed in the laminin-treated integrin-null EBs. Sign In or Create an Account. Advanced Search. User Tools. Sign In. Skip Nav Destination Article Navigation. Articles June 24 Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation Shaohua Li , Shaohua Li.

This Site. Google Scholar. David Harrison , David Harrison. Salvatore Carbonetto , Salvatore Carbonetto. Neil Smyth , Neil Smyth.

David Edgar , David Edgar. Peter D. Yurchenco Peter D. Author and Article Information. Shaohua Li. David Harrison. Salvatore Carbonetto. Neil Smyth. Together, our results suggest that gene duplication and loss and domain shuffling and loss all played a role in the evolution of the laminin family and contributed to the generation of lineage-specific diversity in the laminin gene complements of extant metazoans. Most animals are covered by a selectively permeable epithelial cell layer.

Internal cavities and organs are also often lined by an epithelial sheet. In bilaterians, epithelial cells 1 exhibit an apical—basal polarity, 2 form cohesive belt-form junctions with adjacent epithelial cells, and 3 are connected to an extracellular matrix ECM at their basal surface, although there are also cases of apical attachment Tyler In general, the genes responsible for determining these epithelial features appear to be conserved between insects, nematodes, and vertebrates Hutter et al.

A majority of these genes are present in the genomes of representative species of the earlier branching cnidarian and placozoan lineages Putnam et al. Recently, it has been shown that most of the genes encoding proteins that establish apical—basal polarity and adherens junctions also exist in the genome of the demosponge, Amphimedon queenslandica , a representative of an even earlier diverging phyletic branch of the Metazoa Fahey and Degnan ; Srivastava et al.

In contrast, basal ECM basal lamina protein orthologues i. In vertebrates and other bilaterians, a laminin network forms part of the basal lamina Henrikson et al. In model bilaterians fly, worm, and mammals , laminins are expressed early in embryogenesis concomitant with the first appearance of basal lamina structures and are thought to play a major role in their initial assembly Li et al. Laminin trimers polymerize into a network that provides structural integrity to the basal lamina.

All chains with the exception of some truncated vertebrate-specific forms—see below consist of a Laminin N-terminal domain LamNT , a series of repeated Laminin-type Epidermal Growth Factor domains LamEGF , and a region at or near the C-terminus capable of forming a coiled coil.

Laminin trimerization is mediated by the coiled-coil regions of the constituent chains, which interact to form a triple helix Beck et al.

Conserved cysteines form interchain disulfide bonds at the N- and C-termini of the coiled coil, which help to stabilize this interaction.

Molecular characteristics of laminin chains and heterotrimers. For these typical laminin types, the Drosophila domain architectures are representative, although the numbers of Laminin-type Epidermal Growth Factor LamEGF repeats may vary in other bilaterian proteins.

Domain diagrams are drawn to scale and reflect the locations of features on the primary sequence. Chain features are drawn to scale on the primary sequence, and hence, the diagram does not represent the dimensions of a correctly folded mature trimer.

Domains are colored according to the key in A. Polymerization of laminin heterotrimers into a supportive ECM network appears to involve interactions between the LamNT domains of the three chains and the LamNT domains from surrounding laminin molecules, although little is known about the exact molecular mechanisms for this interaction Cheng et al.

Further stability is imparted to the basal lamina by interactions between the laminin network and a network of Type IV collagen mediated by the cross-linking molecules, perlecan and nidogen Timpl and Brown Hence, while worm and fly possess two distinct forms of the laminin heterotrimer, mammals possess as many as 16, some of which contain truncations in one or all of the N-terminal regions or short arms. Little is known about the evolution of the laminin gene family.

The ECM is a metazoan synapomorphy and, as expected, laminin genes and their characteristic domains are not found in fully sequenced genomes from fungi, plants, and non-opisthokont unicellular eukaryotes King et al. As with several other important ECM domains, the laminin domains, LamNT and LamG, are present in the genome of the choanoflagellate, Monosiga brevicollis , a representative of the unicellular lineage most closely related to the Metazoa King et al.

Here, we explore the molecular characteristics of the complete set of laminin-related genes encoded by the genome of the demosponge, A. As a member of phylum Porifera, consistently placed at the base of the metazoan phylogenetic tree by molecular analyses Philippe et al.

We find that all Amphimedon laminins possess unique domain architectures with respect to known bilaterian chain types but still appear to be capable of assembly into higher order structures via formation of coiled coils and interchain disulfide bonds.

In order to gain further insight into the evolution of the metazoan laminin family, we characterized the complete complements of laminin-related genes in the genomes of the choanoflagellate, M.

We also explored the phylogenetic distribution and origin of conserved metazoan gene families that share unique domains with laminins, including the usherin, perlecan, and netrin families. Finally, domain-specific phylogenetic analyses and alignments allowed us to elucidate relationships between the different metazoan laminin chain types and the nonlaminin gene families that share the relevant domains.

Genomic trace and expressed sequence tag EST data for A. Assembled genomic contigs, automated gene predictions, bulk annotations of the automated gene predictions, and an annotated genome browser were also kindly provided by the JGI. As a complementary approach, genomic domain searches were used to detect predicted proteins containing relevant laminin domains e.

For S. Sequences for D. For Paircoil2, parameters were set to default with the exception of the P -score threshold, which was adjusted to 0. Newly identified laminin-related proteins that lacked domains in comparable locations to those found in bilaterian laminins were carefully analyzed to ensure that these absences were not due to sequence divergence or errors in gene prediction.

Stretches of coding sequence with no conserved domains were scanned for the presence of low scoring or below threshold domains using the databases specified above. Surrounding and intronic noncoding sequence was checked with BLASTx to ensure that the prediction incorporated all relevant coding sequence.

Sequence alignments were constructed with ClustalX v2. Sequences with gaps caused by suspected modeling errors or contig breaks were replaced by alternative models, edited or discarded from the alignment. The Amphimedon genome encodes five laminin-related genes with four distinct domain architectures fig. All genes possess the two sequence characteristics diagnostic for the laminin family, an N-terminal region consisting of a series of LamEGF repeats and a C-terminal region with high probability for coiled-coil formation.

Amphimedon laminins. A Domain diagrams for laminin proteins encoded by the Amphimedon genome. Diagrams are drawn to scale and reflect the locations of features on the primary sequence. Poorly conserved, dubious, or partial domains are denoted by gray outlines, and alignments are provided for these elsewhere supplementary fig.

S1 , Supplementary Material online. The locations of conserved cysteines C that may form interchain disulfide bonds are indicated with arrows. SignalP, N-terminal signal peptide for protein secretion. Refer to figure 1 legend for domain name abbreviations.

B Structure of a hypothetical Amphimedon laminin heterotrimer. A hypothetical laminin trimer composed of the three Amphimedon laminin chains that would impart the most similarity to a typical mammalian laminin heterotrimer i.

No treatment is currently available for this devastating disease. A Facial weakness with an open mouth and reduced facial expression. Patient has developed bilateral elbow-flexion contractures, a fairly common sign in patients with MDC1A.

B Bilateral knee-flexion contractures and lumbar hyperlordosis. C Truncal weakness and neck-flexion weakness lack of head control when the patient is pulled up from a lying position. Informed consent was obtained from the patient's parents for publication of the photographs. These mice display a relatively mild muscular dystrophy and peripheral neuropathy [ 85 , 86 ]. They also exhibit pronounced hind-leg lameness [ 42 , 43 , 83 ].

Hind-limb paralysis depicted with arrow , a result of peripheral neuropathy, is often seen before death. Further features typical of MDC1A include disrupted basement membranes [ 11 ] and increased apoptosis [ 88 , 89 ]. However, this hypothesis was challenged by Hall et al. Both the ubiquitin-proteasome system and the autophagy-lysosome pathway play key roles in protein degradation in skeletal muscle cells [ 94 ].

Defects in both of these degradative systems have also been found in other muscular dystrophies. For example, Duchenne muscular dystrophy pathogenesis may involve proteasomal degradation of dystrophin and the DGC [ 96 ], and autophagy is impaired but not increased as in MDC1A in collagen VI-deficient muscular dystrophy [ 97 ]. Hematoxylin and eosin staining of triceps and diaphragm cross-sections from a 3.

Changes in the expression of laminin receptors might also contribute to the pathology of MDC1A. Moll et al. Several strategies to combat disease in MDC1A mouse models have been explored during the past decade. Importantly, it was also found that mini-agrin can slow down the progression of disease at every stage [ , , ]. The reduction in muscle fibrosis was particularly marked in these animals.

Additional file 1: Supplemental video 1. The rescue mouse is denoted with a blue pointer at the beginning of the f. Both mice were placed in a new cage. Despite significant therapeutic benefits in mice, it is important to realize that these transgenic approaches are not clinically feasible.

Notably, systemic gene delivery of mini-agrin improved the overall phenotype and muscle function in treated animals [ ]. Several approaches aimed at assuaging the secondary defects in MDC1A, instead of targeting the primary deficiency, have also been undertaken.

Overexpression of Bcl-2 had no major effect in dystrophin-deficient mice, indicating that Bclmediated apoptosis is a more significant contributor to the pathogenesis of MDC1A than that of Duchenne muscular dystrophy [ ].

The same group also recently explored the use of anti-apoptotic pharmacologic treatment. This is a typical feature of abnormal opening of the permeability transition pore caused by a strong increase in intracellular calcium which may be detrimental for the muscle cell.

Persistent opening may cause mitochondrial rupture and subsequent cell death. Finally, cell therapy has been evaluated in mouse models of MDC1A. Moreover, bearing in mind that MDC1A is associated with peripheral neuropathy, therapies that also alleviate the neurologic dysfunction should be favored.

In addition, inactivation of Bax s [ ] and treatment with doxycycline [ ] were reported to be beneficial for the condition of motor neuron. Analysis of these organs has been hampered by the relatively early death of the animals.

Furthermore, the targeted genetic elimination of individual laminin domains in particular the LG domains would be valuable to understand their role in vivo. KIG is a post-doctoral student at the Department of Experimental Medical Science, University of Lund, with a PhD in cell and molecular biology, specializing in preclinical studies of laminins and muscle disease.

MD is a professor in muscle biology at the Department of Experimental Medical Science, University of Lund, with a PhD in animal physiology, specializing in preclinical studies of laminins and muscle disease.

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