Drosophila basement membrane collagen col4a1 mutations cause severe myopathy

Kelemen-Valkony, Ildikó; Kiss, Márton; Csiha, Judit; Kiss, A.; Bircher, Urs; Szidonya, János; Maróy, Péter; Juhász, Gábor; Komonyi, Orbán; Csiszár, Katalin; Mink, Mátyás

doi:10.1016/j.matbio.2011.09.004

Cited by 39 publications

(69 citation statements)

References 55 publications

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“…Embryos homozygous for the deficiency Df(2L)Exel7022 , which deletes both of the Drosophila collagen IV genes, Cg25C and viking ( vkg ), have an alary muscle phenotype comparable to that of Cg25C S3064 /Df(2L)Exel7022 , although with lower penetrance (Figure 3E, Table 1). Notably, we also detect alary muscle detachment in homozygotes for the previously reported allele Cg25C DTS-L3 (data not shown; [30]) and in Cg25C DTS-L3 /Cg25C S3064 embryos (Figure 3F, Table 1). …”

Section: Resultssupporting

confidence: 79%

“…Since several collagen alleles including Cg25C DTS-L3 were recently reported to be associated with temperature-sensitivity [30] we reinvestigated the alary muscle phenotype and viability in selected genotypes at different temperatures. As noted before, the detachment phenotype was not fully penetrant for some trans-allelic Cg25C combinations at our standard temperature of 25°C or below.…”

Section: Resultsmentioning

confidence: 99%

“…Collagens are secreted as homo- or heterotrimeric protomers, with genuine type IV collagens predominantly if not exclusively being found as heterotrimers [26,27]. Based on the conservation of at least two collagen IV genes in diverse organisms such as Drosophila , the nematode Caenorhabditis elegans and humans as well as on genetic data it is assumed that Drosophila collagen IV is also a heterotrimer consisting of two Cg25C -encoded α1 chains and one α2 chain encoded by vkg , analogous to the most common vertebrate type IV collagen α1 2 α2 1 [28-30]. Laminins are secreted as heterotrimeric glycoproteins and formed by dimerization of one β chain and one γ chain, followed by addition of an α chain [31-33].…”

Section: Introductionmentioning

confidence: 99%

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Distinct functions of the laminin β LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila

2014

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BackgroundThe Drosophila heart (dorsal vessel) is a relatively simple tubular organ that serves as a model for several aspects of cardiogenesis. Cardiac morphogenesis, proper heart function and stability require structural components whose identity and ways of assembly are only partially understood. Structural components are also needed to connect the myocardial tube with neighboring cells such as pericardial cells and specialized muscle fibers, the so-called alary muscles.ResultsUsing an EMS mutagenesis screen for cardiac and muscular abnormalities in Drosophila embryos we obtained multiple mutants for two genetically interacting complementation groups that showed similar alary muscle and pericardial cell detachment phenotypes. The molecular lesions underlying these defects were identified as domain-specific point mutations in LamininB1 and Cg25C, encoding the extracellular matrix (ECM) components laminin β and collagen IV α1, respectively. Of particular interest within the LamininB1 group are certain hypomorphic mutants that feature prominent defects in cardiac morphogenesis and cardiac ECM layer formation, but in contrast to amorphic mutants, only mild defects in other tissues. All of these alleles carry clustered missense mutations in the laminin LN domain. The identified Cg25C mutants display weaker and largely temperature-sensitive phenotypes that result from glycine substitutions in different Gly-X-Y repeats of the triple helix-forming domain. While initial basement membrane assembly is not abolished in Cg25C mutants, incorporation of perlecan is impaired and intracellular accumulation of perlecan as well as the collagen IV α2 chain is detected during late embryogenesis.ConclusionsAssembly of the cardiac ECM depends primarily on laminin, whereas collagen IV is needed for stabilization. Our data underscore the importance of a correctly assembled ECM particularly for the development of cardiac tissues and their lateral connections. The mutational analysis suggests that the β6/β3/β8 interface of the laminin β LN domain is highly critical for formation of contiguous cardiac ECM layers. Certain mutations in the collagen IV triple helix-forming domain may exert a semi-dominant effect leading to an overall weakening of ECM structures as well as intracellular accumulation of collagen and other molecules, thus paralleling observations made in other organisms and in connection with collagen-related diseases.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct functions of the laminin β LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila

2014

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“…Striated muscle BM contains from the a1a2(IV) collagen IV network. Morphologic alterations of myofibers and muscular functional defects were observed in Drosophila Col4a1 mutant series, 23 as well as an increase of serum CK and an increase of centronucleated fibers in Col4a1 þ/Dex41 N-ethyl N-nitrosourea mutant mice. 24 We now show that Col4a1 G498V animals have morphologic defects that share characteristics with inherited muscular dystrophies, which are characterized by a disruption of the sarcolemmaeECM connection related to intracellular, transmembrane, or extracellular protein mutations.…”

Section: Discussionmentioning

confidence: 96%

HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect

Guiraud

Migeon

Ferry

et al. 2017

The American Journal of Pathology

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“…Because knocking down or mutating laminin, collagen IV, or perlecan is lethal in Drosophila [13,33,34], we used the temperature sensitive Gal4-Gal80 ts system to express dsRNA against each basement membrane component ubiquitously throughout larvae (with Tub-Gal4 ), depleting the animals of newly synthesized basement membrane protein after embryogenesis. Each larva was allowed to grow to 3 rd instar, wounded, and allowed to recover for 24h (see Experimental Procedures).…”

Section: Resultsmentioning

confidence: 99%

A scar-like lesion is apparent in basement membrane after wound repair in vivo

2018

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Basement membrane is a highly conserved sheet-like extracellular matrix in animals, underlying simple and complex epithelia, and wrapping around tissues like muscles and nerves. Like the tissues they support, basement membranes become damaged by environmental insults. Although it is clear that basement membranes are repaired after damage, virtually nothing is known about this process. For example, it is not known how repaired basement membranes compare to undamaged ones, whether basement membrane components are necessary for epithelial wound closure, or whether there is a hierarchy of assembly that repairing basement membranes follow, similar to the hierarchy of assembly of embryonic basement membranes. In this report, we address these questions using the basement membrane of the Drosophila larval epidermis as a model system. By analyzing the four main basement membrane proteins – laminin, collagen IV, perlecan, and nidogen – we find that although basement membranes are repaired within a day after mechanical damage in vivo, thickened and disorganized matrix scars are evident with all four protein components. The new matrix proteins that repair damaged basement membranes are provided by distant adipose and muscle tissues rather than by the local epithelium, the same distant tissues that provide matrix proteins for growth of unwounded basement membranes. To identify a hierarchy of repair, we tested the dependency of each of the basement membrane proteins on the others for incorporation after damage. For proper incorporation after damage, nidogen requires laminin, and perlecan requires collagen IV, but surprisingly collagen IV does not to depend on laminin. Thus, the rules of basement membrane repair are subtly different than those for de novo assembly.

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Drosophila basement membrane collagen col4a1 mutations cause severe myopathy

Cited by 39 publications

References 55 publications

Distinct functions of the laminin β LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila

Distinct functions of the laminin β LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila

HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect

A scar-like lesion is apparent in basement membrane after wound repair in vivo

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