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The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance.

Ackley BD, Crew JR, Elamaa H, Pihlajaniemi T, Kuo CJ, Kramer JM - J. Cell Biol. (2001)

Bottom Line: The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system.In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain.These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.

ABSTRACT
Type XVIII collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell migration and axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans.

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cle-1 Gene and protein structures. (A) Genomic structure of cle-1 (sequence data available from GenBank/EMBL/DDBJ under accession number AF164959). Exons are indicated as boxes; introns, as lines. Form A–specific exons are red, exons common to forms A and B are dark green, and exons common to all forms are dark blue. The predicted translation start site of each isoform is indicated by an arrow. Splicing patterns for inclusion of the form B– or C–specific first exons (light green or light blue, respectively) are indicated above the intron/exon structure, and splicing patterns for the longer forms, lacking these exons, are below. The four introns that are conserved in cle-1 and mammalian type XVIII and XV collagens are marked with arrowheads. Extents of CLE-1 protein domains are indicated below the structure, and extents of the cg120 deletion are indicated above. (B) CLE-1A domain structure and relatedness to mouse type XVIII collagen and C. elegans UNC-40. Homologous domains are indicated with the same colors. Percentages of amino acid sequence identity and similarity are indicated in the relevant CLE-1A domains (identity/similarity). The regions connecting the thrombospondin (TSP)-related and ES domains to the Gly-X-Y repeats are 34% similar between CLE-1 and type XVIII collagen. (C) Alignment of CLE-1A fibronectin type III (FNIII) repeats with C. elegans UNC-40 (AAB17088), Drosophila Frazzled (AAC47314.1), mouse DCC (P70211), and mouse neogenin (CAA70727.1). (D) Alignment of CLE-1A TSP-related motifs with mouse collagen types XVIII (AAC52903) and XV (AAC53387). (E) Alignment of the CLE-1A COOH-terminal domain with mouse ES (Col XVIII) and restin (Col XV). The four amino acid loop containing Arg158 (arrowhead) is present in CLE-1 and type XVIII collagen but not type XV collagen.
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Figure 1: cle-1 Gene and protein structures. (A) Genomic structure of cle-1 (sequence data available from GenBank/EMBL/DDBJ under accession number AF164959). Exons are indicated as boxes; introns, as lines. Form A–specific exons are red, exons common to forms A and B are dark green, and exons common to all forms are dark blue. The predicted translation start site of each isoform is indicated by an arrow. Splicing patterns for inclusion of the form B– or C–specific first exons (light green or light blue, respectively) are indicated above the intron/exon structure, and splicing patterns for the longer forms, lacking these exons, are below. The four introns that are conserved in cle-1 and mammalian type XVIII and XV collagens are marked with arrowheads. Extents of CLE-1 protein domains are indicated below the structure, and extents of the cg120 deletion are indicated above. (B) CLE-1A domain structure and relatedness to mouse type XVIII collagen and C. elegans UNC-40. Homologous domains are indicated with the same colors. Percentages of amino acid sequence identity and similarity are indicated in the relevant CLE-1A domains (identity/similarity). The regions connecting the thrombospondin (TSP)-related and ES domains to the Gly-X-Y repeats are 34% similar between CLE-1 and type XVIII collagen. (C) Alignment of CLE-1A fibronectin type III (FNIII) repeats with C. elegans UNC-40 (AAB17088), Drosophila Frazzled (AAC47314.1), mouse DCC (P70211), and mouse neogenin (CAA70727.1). (D) Alignment of CLE-1A TSP-related motifs with mouse collagen types XVIII (AAC52903) and XV (AAC53387). (E) Alignment of the CLE-1A COOH-terminal domain with mouse ES (Col XVIII) and restin (Col XV). The four amino acid loop containing Arg158 (arrowhead) is present in CLE-1 and type XVIII collagen but not type XV collagen.

Mentions: The cle-1 gene (collagen with ES domain) is the only homologue of vertebrate type XV/XVIII collagens in the C. elegans genome. cle-1 is a complex gene using three promoters and alternative splicing to generate at least three mRNAs designated cle-1A-C (Fig. 1). Each CLE-1 isoform has a unique first exon beginning with a predicted signal peptide. All isoforms share the collagenous Gly-X-Y repeat domain and COOH-terminal domain with 55% similarity to mouse ES (Fig. 1B and Fig. E). The CLE-1A and -B forms add a region with 35% similarity to vertebrate type XV/XVIII collagens that is related to the NH2-terminal thrombospondin domain also found in collagens IX, XVI, and XIX (Fig. 1B and Fig. D). The CLE-1A–specific NH2-terminal domain contains two fibronectin type III (FNIII) repeats with 40% similarity to the fourth and fifth repeats in the UNC-40/DCC family of netrin receptors (Fig. 1B and Fig. C).


The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance.

Ackley BD, Crew JR, Elamaa H, Pihlajaniemi T, Kuo CJ, Kramer JM - J. Cell Biol. (2001)

cle-1 Gene and protein structures. (A) Genomic structure of cle-1 (sequence data available from GenBank/EMBL/DDBJ under accession number AF164959). Exons are indicated as boxes; introns, as lines. Form A–specific exons are red, exons common to forms A and B are dark green, and exons common to all forms are dark blue. The predicted translation start site of each isoform is indicated by an arrow. Splicing patterns for inclusion of the form B– or C–specific first exons (light green or light blue, respectively) are indicated above the intron/exon structure, and splicing patterns for the longer forms, lacking these exons, are below. The four introns that are conserved in cle-1 and mammalian type XVIII and XV collagens are marked with arrowheads. Extents of CLE-1 protein domains are indicated below the structure, and extents of the cg120 deletion are indicated above. (B) CLE-1A domain structure and relatedness to mouse type XVIII collagen and C. elegans UNC-40. Homologous domains are indicated with the same colors. Percentages of amino acid sequence identity and similarity are indicated in the relevant CLE-1A domains (identity/similarity). The regions connecting the thrombospondin (TSP)-related and ES domains to the Gly-X-Y repeats are 34% similar between CLE-1 and type XVIII collagen. (C) Alignment of CLE-1A fibronectin type III (FNIII) repeats with C. elegans UNC-40 (AAB17088), Drosophila Frazzled (AAC47314.1), mouse DCC (P70211), and mouse neogenin (CAA70727.1). (D) Alignment of CLE-1A TSP-related motifs with mouse collagen types XVIII (AAC52903) and XV (AAC53387). (E) Alignment of the CLE-1A COOH-terminal domain with mouse ES (Col XVIII) and restin (Col XV). The four amino acid loop containing Arg158 (arrowhead) is present in CLE-1 and type XVIII collagen but not type XV collagen.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199198&req=5

Figure 1: cle-1 Gene and protein structures. (A) Genomic structure of cle-1 (sequence data available from GenBank/EMBL/DDBJ under accession number AF164959). Exons are indicated as boxes; introns, as lines. Form A–specific exons are red, exons common to forms A and B are dark green, and exons common to all forms are dark blue. The predicted translation start site of each isoform is indicated by an arrow. Splicing patterns for inclusion of the form B– or C–specific first exons (light green or light blue, respectively) are indicated above the intron/exon structure, and splicing patterns for the longer forms, lacking these exons, are below. The four introns that are conserved in cle-1 and mammalian type XVIII and XV collagens are marked with arrowheads. Extents of CLE-1 protein domains are indicated below the structure, and extents of the cg120 deletion are indicated above. (B) CLE-1A domain structure and relatedness to mouse type XVIII collagen and C. elegans UNC-40. Homologous domains are indicated with the same colors. Percentages of amino acid sequence identity and similarity are indicated in the relevant CLE-1A domains (identity/similarity). The regions connecting the thrombospondin (TSP)-related and ES domains to the Gly-X-Y repeats are 34% similar between CLE-1 and type XVIII collagen. (C) Alignment of CLE-1A fibronectin type III (FNIII) repeats with C. elegans UNC-40 (AAB17088), Drosophila Frazzled (AAC47314.1), mouse DCC (P70211), and mouse neogenin (CAA70727.1). (D) Alignment of CLE-1A TSP-related motifs with mouse collagen types XVIII (AAC52903) and XV (AAC53387). (E) Alignment of the CLE-1A COOH-terminal domain with mouse ES (Col XVIII) and restin (Col XV). The four amino acid loop containing Arg158 (arrowhead) is present in CLE-1 and type XVIII collagen but not type XV collagen.
Mentions: The cle-1 gene (collagen with ES domain) is the only homologue of vertebrate type XV/XVIII collagens in the C. elegans genome. cle-1 is a complex gene using three promoters and alternative splicing to generate at least three mRNAs designated cle-1A-C (Fig. 1). Each CLE-1 isoform has a unique first exon beginning with a predicted signal peptide. All isoforms share the collagenous Gly-X-Y repeat domain and COOH-terminal domain with 55% similarity to mouse ES (Fig. 1B and Fig. E). The CLE-1A and -B forms add a region with 35% similarity to vertebrate type XV/XVIII collagens that is related to the NH2-terminal thrombospondin domain also found in collagens IX, XVI, and XIX (Fig. 1B and Fig. D). The CLE-1A–specific NH2-terminal domain contains two fibronectin type III (FNIII) repeats with 40% similarity to the fourth and fifth repeats in the UNC-40/DCC family of netrin receptors (Fig. 1B and Fig. C).

Bottom Line: The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system.In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain.These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.

ABSTRACT
Type XVIII collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell migration and axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans.

Show MeSH
Related in: MedlinePlus