Genomic structure and embryonic expression of zebrafish lysyl hydroxylase 1 and lysyl hydroxylase 2

Schneider, Valérie; Granato, Michael

doi:10.1016/j.matbio.2006.09.007

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Three LH isoforms, LH1, LH2a/2b and LH3, originating from three different genes, have been characterized so far from human, mouse, rat and zebrafish [13][14][15][16][17][18][19][20][21]. We have demonstrated that LH3 and C. elegans LH, the only ortholog for lysyl hydroxylase in the nematode, are multi-functional enzymes possessing LH, GT and GGT activities in vitro [21][22][23][24].…”

Section: Introductionmentioning

confidence: 94%

The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability

Wang

Kovanen

Raudasoja

et al. 2009

J Cellular Molecular Medi

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Lysyl hydroxylase (LH) isoform 3 is a post-translational enzyme possessing LH, collagen galactosyltransferase (GT) and glucosyltransferase (GGT) activities. We have demonstrated that LH3 is found not only intracellularly, but also on the cell surface and in the extracellular space, suggesting additional functions for LH3. Here we show that the targeted disruption of LH3 by siRNA causes a marked reduction of both glycosyltransferase activities, and the overexpression of LH3 in HT-1080 cells increases hydroxylation of lysyl residues and the subsequent galactosylation and glucosylation of hydroxylysyl residues. These data confirm the multi-functionality of LH3 in cells. Furthermore, treatment of cells in culture medium with a LH3 N-terminal fragment affects the cell behaviour, rapidly leading to arrest of growth and further to lethality if the fragment is glycosyltransferase-deficient, and leading to stimulation of proliferation if the fragment contains LH3 glycosyltransferase activities. The effect is reversible, the cells recovering after removal of the glycosyltransferase-deficient fragment. The findings were confirmed by overexpressing the full-length LH3 in native or mutated forms in the cells. The data indicate that the increase in proliferation depends on the glycosyltransferase activity of LH3. The overexpression of a glycosyltransferase-deficient mutant or targeted disruption of LH3 by siRNA in cells results in abnormal cell morphology followed by cell death. Our data clearly indicate that the deficiency of LH3 glycosyltransferase activities, especially in the extracellular space, causes growth arrest revealing the importance of the glycosyltransferase activities of LH3 for cell growth and viability, and identifying LH3 as a potential target for medical applications, such as cancer therapy.

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Section: Introductionmentioning

confidence: 94%

The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability

Wang

Kovanen

Raudasoja

et al. 2009

J Cellular Molecular Medi

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“…At the molecular level, both processes are regulated by the expression of apoptotic-or regeneration-associated genes. 23 However, it is still under debate whether regenerating axons rely on environmental cues to guide them toward their original target 27 and which cues are responsible for this process.…”

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confidence: 99%

“…In the brain, on the other hand, only a small amount was detectable and was located intracellularly in the pyramidal cells, while its specific role remains unknown. 25,26 Regarding zebrafish, apart from lh3 being expressed in the peripheral glia, corresponding temporally with motor axon outgrowth, 27 we are not aware of a role in the central nervous system (CNS).…”

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confidence: 99%

It is all about the support — The role of the extracellular matrix in regenerating axon guidance

Roumazeilles

Dokalis

Kaulich

et al. 2018

Cell Adhesion & Migration

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Although it is known for long time that the peripheral nervous system has the capacity for self-regeneration, the molecular mechanisms by which Schwann cells and extracellular matrix (ECM) guide the injured axons to regrow along their original path, remains a poorly understood process. Due to the importance of ECM molecules during development, constitutive mutant organisms display increased lethality, therefore, conditional or inducible strategies have been used to increase the survival of the organisms and allow the study of the role of ECM proteins. In a recent report published in Neuron, Isaacman-Beck and colleagues (2015) used these pioneering genetic studies on zebrafish combined with in vivo fluorescent imaging, to investigate the micro-environmental conditions required for targeted regeneration of the dorsal motor nerve of zebrafish larvae after laser-transection. A candidate gene approach targeting lh3 basal laminar collagen substrates revealed that the lh3 substrate col4α5 regulates dorsal nerve regeneration by destabilizing misdirected axons. Col4α5 was upregulated in a small population of lh3 expressing Schwann cells located ventrally and ventro-laterally to the injury site and found to co-localize with the molecule slit guidance ligand 1 (slit1a). Capitalizing on the crucial observations of mistargeted regeneration of dorsal nerves in mutant larvae, they put forward a model in which Schwann cells shape an environment that allows and directs axonal regeneration to their original synaptic target. In the light of Isaacman-Beck and colleagues (2015) findings, we will review how their study contributes to the research field, and comment on its potential implications for promoting nerve regeneration after injury.

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“…Three lysyl hydroxylase isoforms (LH1, LH2, and LH3) have been identified from human, mouse, rat, and zebrafish (3)(4)(5)(6)(7)(8)(9)(10). In addition, LH2 has two alternatively spliced forms, LH2a (short) and LH2b (long) (11).…”

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confidence: 99%

Reduction of Lysyl Hydroxylase 3 Causes Deleterious Changes in the Deposition and Organization of Extracellular Matrix

Risteli

Ruotsalainen

Salo

et al. 2009

Journal of Biological Chemistry

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Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase, collagen galactosyltransferase, and glucosyltransferase (GGT) activities. We report here an important role for LH3 in the organization of the extracellular matrix (ECM) and cytoskeleton. Deposition of ECM was affected in heterozygous LH3 knock-out mouse embryonic fibroblasts (MEF ؉/؊ ) and in skin fibroblasts collected from a member of a Finnish epidermolysis bullosa simplex (EBS) family known to be deficient in GGT activity. We show the GGT deficiency to be due to a transcriptional defect in one LH3 allele. The ECM abnormalities also lead to defects in the arrangement of the cytoskeleton in both cell lines. Ultrastructural abnormalities were observed in the skin of heterozygous LH3 knock-out mice indicating that even a moderate decrease in LH3 has deleterious consequences in vivo. The LH3 null allele in the EBS family member and the resulting abnormalities in the organization of the extracellular matrix, similar to those found in MEF ؉/؊ , may explain the correlation between the severity of the phenotype and the decrease in GGT activity reported in this family.Lysyl hydroxylase (LH) 2 catalyzes the post-translational formation of hydroxylysines in -X-Lys-Gly-sequences in collagens and other proteins with collagen-like domains (1, 2). Three lysyl hydroxylase isoforms (LH1, LH2, and LH3) have been identified from human, mouse, rat, and zebrafish (3-10). In addition, LH2 has two alternatively spliced forms, LH2a (short) and LH2b (long) (11). Several mutations of the LH1 gene (PLOD1) have been identified in patients with Ehlers-Danlos syndrome (EDS) type VIA, a heritable disorder characterized by kyphoscoliosis, joint laxity, skin fragility, and muscle hypotonia (12, 13). EDS VIA data indicate that LH1 hydroxylates helical crosslinking lysines of type I collagen in bone and type II collagen in cartilage (14,15). Patients with Bruck syndrome, characterized by joint contractures, fragile bones, and osteoporosis, have mutations in the LH2 gene (PLOD2) that result in the complete absence of telopeptide hydroxylysine residues in bone collagens (16,17). In addition, overexpression of LH2b has been linked to an increase in the hydroxylysine content of collagen telopeptides seen in fibrotic disorders (18).LH3 differs from the other lysyl hydroxylase isoforms in that it possesses, in addition to lysyl hydroxylase activity (6, 19), hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase (GGT) activities (20 -22), thus LH3 is able to catalyze the formation of glucosylgalactosylhydroxylysine residues. Recent studies show that LH3 is located not only in the endoplasmic reticulum but also in the extracellular space, and that the GGT activity in serum originates from LH3 (23). Furthermore, LH3 knock-out studies in mice demonstrate that the loss of LH3 leads to embryonic lethality due to disruption of the formation of basement membranes (24,25). Analyses of LH3 knock-out embryos and embryonic fibroblasts indicate that the ...

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Genomic structure and embryonic expression of zebrafish lysyl hydroxylase 1 and lysyl hydroxylase 2

Cited by 14 publications

References 31 publications

The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability

The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability

It is all about the support — The role of the extracellular matrix in regenerating axon guidance

Reduction of Lysyl Hydroxylase 3 Causes Deleterious Changes in the Deposition and Organization of Extracellular Matrix

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