Morpholino knockdown of lysyl oxidase impairs zebrafish development, and reflects some aspects of copper metabolism disorders

Reynaud, Caroline; Baas, Dominique; Gleyzal, Claudine; Guellec, Dominique Le; Sommer, Pascal

doi:10.1016/j.matbio.2008.03.002

Cited by 25 publications

(23 citation statements)

References 61 publications

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“…The expression pattern of zebrafish lox overlaps with that of P4H-TM being expressed in the central nervous system and eyes at 3 dpf, and its morpholino knockdown phenocopies some aspects of the P4H-TM-deficient larvae by showing reduced size of the head and eyes and pericardial edema (42). In addition, these larvae have defects in the organization of their notochord BM, muscle development, and neurogenesis (42). Collagen XVIII-deficient mice have been reported to have alterations in their kidney BMs and kidney filtering capacity (43), and collagen XVIII is required for preservation of the integrity of ECM and capillaries in the kidney (44).…”

Section: Discussionmentioning

confidence: 95%

“…Down-regulation of lox may therefore have contributed to the altered BM structures in P4H-TM-deficient larvae. The expression pattern of zebrafish lox overlaps with that of P4H-TM being expressed in the central nervous system and eyes at 3 dpf, and its morpholino knockdown phenocopies some aspects of the P4H-TM-deficient larvae by showing reduced size of the head and eyes and pericardial edema (42). In addition, these larvae have defects in the organization of their notochord BM, muscle development, and neurogenesis (42).…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function

Hyvärinen

Parikka

Sormunen

et al. 2010

Journal of Biological Chemistry

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Prolyl 4-hydroxylases (P4Hs) catalyze the hydroxylation of collagens and hypoxia-inducible factor (HIF)-␣ subunits. We studied the zebrafish homologue of the recently characterized human transmembrane P4H (P4H-TM) that can hydroxylate HIF-␣, but not collagens, in vitro and influence HIF-␣ levels in cellulo. The zebrafish P4H-TM mRNA had its highest expression in the eye and brain and lower levels in other tissues, including the kidney. Morpholino knockdown of P4H-TM in embryos resulted in a reduction in the size of the eye and head and morphological alterations in the head from 2 days postfertilization onward. In addition, pericardial edema, regarded as a sign of kidney dysfunction, developed from 3 days postfertilization onward. The phenotype was dependent on the P4H-TM catalytic activity because similar results were obtained with morpholinos targeting either translation initiation or catalytic residues of the enzyme. Structural and functional analyses of the morphant pronephric kidneys revealed fragmented glomerular basement membranes (BMs), disorganized podocyte foot processes, and severely compromised pronephric kidney function leading to proteinuria. The opacity of the eye lens was increased due to the presence of extra nuclei and deposits, and the structure of the lens capsule BM was altered.Our data suggest that P4H-TM catalytic activity is required for the proper development of the glomerular and lens capsule BMs. Many HIF target genes were induced in the P4H-TMdeficient morphants, but the observed phenotype is not likely to be mediated at least solely via the HIF pathway, and thus P4H-TM probably has additional, as yet unknown, substrates.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function

Hyvärinen

Parikka

Sormunen

et al. 2010

Journal of Biological Chemistry

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“…Further, Lox knockdown in the zebrafish embryo disturbed somite development, although this was attributed to disruption of the adjacent tissue, the notochord, a regulator of somite organization (Reynaud et al, 2008). Together, these observations suggest that Lox participates in muscle development, although the underlying mechanism is unknown.…”

Section: Loxmentioning

confidence: 97%

Muscle composition is regulated by a Lox-TGFβ feedback loop

et al. 2015

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Muscle is an integrated tissue composed of distinct cell types and extracellular matrix. While much emphasis has been placed on the factors required for the specification of the cells that comprise muscle, little is known about the crosstalk between them that enables the development of a patterned and functional tissue. We find in mice that deletion of lysyl oxidase (Lox), an extracellular enzyme regulating collagen maturation and organization, uncouples the balance between the amount of myofibers and that of muscle connective tissue (MCT). We show that Lox secreted from the myofibers attenuates TGFβ signaling, an inhibitor of myofiber differentiation and promoter of MCT development. We further demonstrate that a TGFβ-Lox feedback loop between the MCT and myofibers maintains the dynamic developmental homeostasis between muscle components while also regulating MCT organization. Our results allow a better understanding of diseases such as Duchenne muscular dystrophy, in which LOX and TGFβ signaling have been implicated and the balance between muscle constituents is disturbed.

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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%

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

171

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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Morpholino knockdown of lysyl oxidase impairs zebrafish development, and reflects some aspects of copper metabolism disorders

Cited by 25 publications

References 61 publications

Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function

Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function

Muscle composition is regulated by a Lox-TGFβ feedback loop

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

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