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1.
Nature ; 499(7458): 306-11, 2013 Jul 18.
Article in English | MEDLINE | ID: mdl-23868260

ABSTRACT

Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-ß1 (TGF-ß1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-ß accessory receptor endoglin, which, in the presence of TGF-ß1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-ß signalling.


Subject(s)
Endothelium, Vascular/metabolism , Glycoproteins/physiology , Retinal Neovascularization/metabolism , Signal Transduction , Transforming Growth Factor beta1/metabolism , Animals , Cells, Cultured , Endothelium, Vascular/cytology , Glycoproteins/genetics , Glycoproteins/metabolism , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Transforming Growth Factor beta/metabolism , Retinal Neovascularization/genetics , Retinal Vessels/metabolism , Transforming Growth Factor beta1/pharmacology
2.
Hum Mol Genet ; 18(3): 472-81, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-18996918

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Genetic Variation , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Motor Neurons/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Adult , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/metabolism , Animals , Drosophila/genetics , Drosophila/metabolism , Female , Genetic Predisposition to Disease , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Mutation , White People/genetics , Zebrafish/genetics , Zebrafish/metabolism
3.
Dev Biol ; 320(1): 289-301, 2008 Aug 01.
Article in English | MEDLINE | ID: mdl-18572157

ABSTRACT

Little is known of the first transcriptional events that regulate neural fate in response to extracellular signals such as Bmps and Fgfs. Sox3 is one of the earliest transcription factors to be expressed in the developing CNS and has been shown to be regulated by these signalling pathways. We have used both gain- and loss-of-function experiments in zebrafish to elucidate the role of Sox3 in determining neural fate. Ectopic Sox3 caused induction of neural tissue from a very early stage of cell specification in the ectoderm and this effect was maintained such that large domains of additional CNS were apparent, including almost complete duplications of the CNS. Knock-down of Sox3 using morpholinos resulted in a reduction in the size of the CNS, ears and eyes and subsequent inhibition of some aspects of neurogenesis. Our data also suggest that the pro-neural effects of Sox3 can compensate for inhibition of Fgf signalling in inducing neural tissue but it is not sufficient to maintain neural fate, suggesting the presence of Sox3-independent roles of Fgf at later stages.


Subject(s)
Cell Differentiation , Cell Lineage , DNA-Binding Proteins/metabolism , Ectoderm/cytology , High Mobility Group Proteins/metabolism , Neurons/cytology , Transcription Factors/metabolism , Zebrafish/embryology , 5' Untranslated Regions/genetics , Animals , Base Sequence , Biomarkers/metabolism , Body Patterning , Central Nervous System/embryology , DNA-Binding Proteins/genetics , Ear/abnormalities , Ear/embryology , Ectoderm/embryology , Embryo, Nonmammalian/cytology , Fibroblast Growth Factors/metabolism , Gene Expression Regulation, Developmental , High Mobility Group Proteins/genetics , Molecular Sequence Data , Neural Plate/cytology , Neurons/metabolism , SOXB1 Transcription Factors , Signal Transduction , Skull/abnormalities , Skull/embryology , Transcription Factors/genetics , Zebrafish/genetics
4.
Science ; 319(5870): 1668-72, 2008 Mar 21.
Article in English | MEDLINE | ID: mdl-18309045

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , DNA-Binding Proteins/genetics , Mutation, Missense , Adult , Amino Acid Sequence , Amino Acid Substitution , Animals , Apoptosis , CHO Cells , Chick Embryo , Chromosomes, Human, Pair 1/genetics , Cricetinae , Cricetulus , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/physiology , Embryonic Development , Female , Humans , Male , Microsatellite Repeats , Middle Aged , Molecular Sequence Data , Mutant Proteins/chemistry , Mutant Proteins/physiology , Neurons/cytology , Neurons/physiology
5.
CNS Neurol Disord Drug Targets ; 7(1): 11-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18289027

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis and respiratory failure. About 1 in every 400 people dies of ALS, usually within 3 to 5 years of symptom onset. The lack of effective therapy means that although the incidence is comparable to that of multiple sclerosis, the prevalence is low. The causes of ALS are largely unknown, but the only disease-modifying therapy, riluzole, was designed based on one hypothesis of disease causation, the excitotoxic hypothesis. In this paper we will review current ideas about the causes of ALS and the therapeutic opportunities they suggest.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/therapy , Amyotrophic Lateral Sclerosis/epidemiology , Animals , Cell Death/physiology , Humans , Models, Biological , Neuroprotective Agents/therapeutic use , Riluzole/therapeutic use
6.
Dev Biol ; 303(2): 675-86, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17222818

ABSTRACT

The epibranchial placodes are cranial, ectodermal thickenings that give rise to sensory neurons of the peripheral nervous system. Despite their importance in the developing animal, the signals responsible for their induction remain unknown. Using the placodal marker, sox3, we have shown that the same Fgf signaling required for otic vesicle development is required for the development of the epibranchial placodes. Loss of both Fgf3 and Fgf8 is sufficient to block placode development. We further show that epibranchial sox3 expression is unaffected in mutants in which no otic placode forms, where dlx3b and dlx4b are knocked down, or deleted along with sox9a. However, the forkhead factor, Foxi1, is required for both otic and epibranchial placode development. Thus, both the otic and epibranchial placodes form in a common region of ectoderm under the influence of Fgfs, but these two structures subsequently develop independently. Although previous studies have investigated the signals that trigger neurogenesis from the epibranchial placodes, this represents the first demonstration of the signaling events that underlie the formation of the placodes themselves, and therefore, the process that determines which ectodermal cells will adopt a neural fate.


Subject(s)
Fibroblast Growth Factors/metabolism , Peripheral Nerves/embryology , Peripheral Nerves/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Zebrafish/metabolism , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Ectoderm/cytology , Ectoderm/metabolism , Fibroblast Growth Factor 3/genetics , Fibroblast Growth Factor 3/metabolism , Fibroblast Growth Factors/genetics , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental , High Mobility Group Proteins/genetics , High Mobility Group Proteins/metabolism , In Situ Hybridization , Models, Biological , Mutation , Neurons, Afferent/cytology , Neurons, Afferent/metabolism , SOXB1 Transcription Factors , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Zebrafish/genetics , Zebrafish Proteins/genetics
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