Essential role of lysyl oxidases in notochord development

Gansner, John M.; Mendelsohn, Bryce A.; Hultman, Keith A.; Johnson, Stephen L.; Gitlin, Jonathan D.

doi:10.1016/j.ydbio.2007.04.029

Cited by 80 publications

(95 citation statements)

References 52 publications

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“…Previous reports have suggested the existence of a negative feedback signaling mechanism that monitors the formation of the notochord collagen sheath (Anderson et al, 2007;Gansner et al, 2007). Inhibition of collagen crosslinking by copper chelation, direct inhibition of lysyl oxidase, or knockdown of lysyl oxidase mRNAs results in a characteristic kinked notochord and abnormally persistent expression of col2a1, similar to what we observe in polycystin morphants (Anderson et al, 2007;Gansner et al, 2007).…”

Section: Research Articlesupporting

confidence: 88%

“…Inhibition of collagen crosslinking by copper chelation, direct inhibition of lysyl oxidase, or knockdown of lysyl oxidase mRNAs results in a characteristic kinked notochord and abnormally persistent expression of col2a1, similar to what we observe in polycystin morphants (Anderson et al, 2007;Gansner et al, 2007). To better define the nature of the feedback signals regulating notochord collagen expression, we knocked down col2a1 and assayed the expression of the remaining notochord collagens, col9a2 and col27a1.…”

Section: Research Articlesupporting

confidence: 52%

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The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Mangos

Lam

Zhao

et al. 2010

Disease Models &Amp; Mechanisms

136

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SUMMARYMutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b-and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

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Section: Research Articlesupporting

confidence: 88%

Section: Research Articlesupporting

confidence: 52%

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Mangos

Lam

Zhao

et al. 2010

Disease Models &Amp; Mechanisms

136

View full text Add to dashboard Cite

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“…␤-APN treatment of 3 hpf embryos resulted in striking notochord distortion ( Figure 4F), a defect involving LOX, LOXL1, and LOXL5b, 27,29 and altered vascular patterning with distortion of the DA and irregular distribution of ISV ( Figure 4H). Even though ISV have all migrated to the dorsal roof and formed the DLAV, embryos displayed very variable number of perfused ISV at 48 hpf ( Figure 4G).…”

Section: Loxl2 Participates To Intersegmental Vessel Formation In Zebmentioning

confidence: 99%

“…Zebrafish genome encodes 2 loxl2 genes (loxl2a and loxl2b). Whereas loxl2b expression is initiated during early development throughout the notochord and extinguished between 24 and 48 hours after fertilization (hpf), 27 the expression pattern of loxl2a has not been reported yet. Loxl2a mRNA increased between 20 and 48 hpf and was detected in ISV ( Figure 4A-B).…”

Section: Loxl2 Participates To Intersegmental Vessel Formation In Zebmentioning

confidence: 99%

Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane

Bignon

Pichol-Thievend

Hardouin

et al. 2011

Blood

172

173

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Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. IntroductionAngiogenesis occurs during development and tissue remodeling, and in the pathologic context of cardiovascular ischemic diseases or tumor growth. Sprouting of new vessels is initiated by stimulation of endothelial cells (ECs) by a combination of signals from the microenvironment that includes oxygen tension and growth factors. Cells from not yet vascularized tissue and ECs that invade this microenvironment are both hypoxia targets through the Hypoxia Inducible Factor (HIF) pathway. HIF activates transcription of genes coding for autocrine/paracrine factors like vascular endothelial growth factor (VEGF) and extracellular matrix (ECM) components. 1 Synergy between these responses is assumed through local concentration of growth factors in the ECM where they function as attractant for ECs. Specialized ECs, called tip cells, lead vascular growth by sending out filopodia to explore the hypoxic microenvironment. 2 Tip cells are thus continuously exposed to low oxygen concentration. 3 Stalk cells, located behind the tip cells, serve to vessel growth by proliferation, lumen formation and junction establishment. 4 Vascular ECM undergoes major remodeling during angiogenesis, consisting in ECM/basement membrane degradation, provisional ECM generation and assembly of a new basement membrane. ECM-mediated mechanotransductive signaling regulates 3D multicellular organization, including lumen formation and tubulogenesis. Thus, in addition to storing angiogenic factors and providing structural features, ECM is a dynamic promoter of angiogenesis. 5 Subendothelial basement membrane is composed of nonfibrillar collagen IV, laminin, perlecan and nidogens. Other collagens (VIII, XV, and XVIII), fibronectin and matricellular proteins (thrombospondin-1, Cyr61) are associated with the basement membrane. There is only little data concerning the assembly of the vascular microenvironment and its impact on angiogenesis. Genes encoding ECM components and enzymes involved in their assembly and stabilization are targets of hypoxia in ECs. 1 To identify key regulators of the angiogenesis-associated ECM remodeling, we performed a proteomic analysis of endothelial ECM generated in vitro under hypoxic conditions. We found that the ECM cross-linking enzyme, lysyl oxidase-like protein-2 (LOXL2) is a major target of hypoxia. Lysyl oxidases, consisting in lysyl oxidase (LOX) and 4 lysyl oxidase-like proteins (LOXL 1 to 4), catalyze the deamination of lysines and hydroxylysines, generating aldehydes that spontaneously react to form co...

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“…Assays in zebrafish with drugs that chelate copper show that the notochord is extremely sensitive to this deficiency, a phenotype shown to be due to the inactivation of the cuproenzyme lysyl oxidase (14). The essentiality of this micronutrient was also shown genetically, as a mutation in the atp7a transporter, the Menkes disease gene, produces a similar phenotype (15).…”

Section: Copper Handling In the Zebrafish Embryo And Larvamentioning

confidence: 99%

Zebrafish (Danio rerio) as a model for studying the genetic basis of copper toxicity, deficiency, and metabolism

Hernández

Allende

2008

The American Journal of Clinical Nutrition

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Unicellular eukaryotes and cultured cells from several animal species were invaluable in discovering the mechanisms that govern incorporation, handling, and excretion of copper at the cellular level. However, understanding the systemic regulation of copper availability and distribution among the different tissues of an intact multicellular organism has proven to be more challenging. This analysis is made even more difficult if the genetic variability among organisms is taken into account. The zebrafish has long been considered a powerful animal model because of its tractable genetics and embryology, but it has more recently become a player in environmental studies, pharmaceutical screening, and physiologic analysis. In particular, the use of the larvae, small enough to fit into a microtiter well, but developed enough to have full organ functionality, represents a convenient alternative for studies that aim to establish effects of environmental agents on the intact, living organism. Studies by our group and others have characterized absorption and tissue distribution of copper and have described the acute effects of the metal on larvae in terms of survival, organ stress, and functionality of sensory organs. A large body of work has shown that there is strong conservation in mechanisms and genes between fish and mammals, opening the possibility for genetic or small molecule screens or for generating fish models of human diseases related to copper metabolism. The variability within humans in terms of tolerance to copper excess or deficiency requires a genetic approach to be taken to understand the behavior of populations, because markers and vulnerabilities need to be identified. The zebrafish could represent a unique tool to move in this direction.Am J Clin Nutr 2008;88(suppl): 835S-9S.

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Essential role of lysyl oxidases in notochord development

Cited by 80 publications

References 52 publications

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane

Zebrafish (Danio rerio) as a model for studying the genetic basis of copper toxicity, deficiency, and metabolism

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