64 research outputs found
Ode À Cassandre
No full textEn avril 1545, Ronsard rencontre, dans une fête à la cour, Cassandre Salviati, fille d’un banquier italien dont il tombera amoureux. Ronsard a 20 ans et Cassandre en a 13. Lorsqu’elle quitte la cour, le lendemain, Ronsard en gardera un beau souvenir. Il compose ce poème en souvenir d’elle. Le poème, sous forme d’une ode, est un exercice de cour plutôt banal mais il reste original par sa vivacité et l’image de l'amour qu'il donne
Expression and role of the orphan nuclear receptor NR5A2 in mouse embryogenesis and female reproductive function
No full textThe orphan nuclear receptor NR5A2 is implicated in a multitude of biological processes including cholesterol homeostasis and development. Its role in cholesterol metabolism and cell proliferation is now well established in vitro and in vivo. Both in vitro and gene expression studies have suggested a role for NR5A2 in ovarian function. In this study, we provide in vivo evidence for its involvement in reproductive function by demonstrating that heterozygosity for a null mutation of NR5A2 leads to a reduction in female fertility. Furthermore, we showed that NR5A2+/- females display a severe reduction in ovarian progesterone production and that progesterone supplementation can rescue the NR5A2+/- subfertility phenotype. We also provide evidence that one of the mechanisms by which NR5A2 regulates ovarian progesterone production is through modulating the expression of SCAR, which controls one of the rate-limiting steps of progesterone synthesis.A targeted disruption of the NR5A2 gene in the mouse leads to early lethality in utero between embryonic days 6.0 and 7.5, showing that NR5A2 plays a crucial role during early embryogenesis. The molecular mechanisms underlying this early lethality, however, are poorly understood. In this study, we used a morphological and marker gene analysis to characterize the NR5A2-/- embryonic phenotype and showed that although initial axis specification occurs in NR5A2-/- embryos, primitive streak and mesoderm fail to form. Using a chimeric approach, we demonstrated a requirement for NR5A2 function in the visceral endoderm (VE), an extra-embryonic tissue, for proper primitive streak morphogenesis and gastrulation. Our results also indicate a reduction in the expression of VE marker genes involved in the nutritive function of this tissue, suggesting that NR5A2 play a dual role in the VE, being implicated in the mediation of both its patterning and nutritive activity.Taking advantage of the LacZ knock-in approach used to inactivate the NR5A2 gene, we also demonstrated that NR5A2 is expressed during craniofacial and nervous system development, suggesting a novel role for NR5A2 in head formation and neural development
Use of sodium 4-phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in Col4a1 mutant mice
No full textCollagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers that constitute a major component of nearly all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that includes variable cerebrovascular and skeletal muscle manifestations. The pathogenicity of COL4A1 and COL4A2 mutations is generally attributed to impaired secretion into basement membranes. Sodium 4-phenylbutyrate (4PBA) is a US Food and Drug Administration-approved drug that promotes mutant heterotrimer secretion in vitro and in vivo. Here, we use different 4PBA treatment paradigms to define therapeutic parameters for preventing cerebrovascular and muscular pathologies in Col4a1 mutant mice. We show the efficacy of long-term 4PBA treatment in reducing the severity of intracerebral hemorrhages (ICHs) in Col4a1 mutant mice aged up to 8 months. In addition, we demonstrate that maximal efficacy of 4PBA on ICH and myopathy was achieved when treatment was initiated prenatally, whereby even transient 4PBA administration had lasting benefits after being discontinued. Importantly, postnatal treatment with 4PBA also reduced ICH and skeletal myopathy severities in Col4a1 mutant mice, which has significant clinical implications for patients with COL4A1 and COL4A2 mutations. This article has an associated First Person interview with the first author of the paper
D.B.: COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets
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COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets
No full textHeterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches
COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets
No full textUse of 4-phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in <i>Col4a1</i> mutant mice
No full textCollagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers that constitute a major component of nearly all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that includes variable cerebrovascular and skeletal muscle manifestations. The pathogenicity of COL4A1 and COL4A2 mutations is generally attributed to impaired secretion into basement membranes. Sodium 4-phenylbutyrate (4PBA) is an FDA-approved drug that promotes mutant heterotrimer secretion in vitro and in vivo. Here, we use different 4PBA treatment paradigms to define therapeutic parameters for preventing cerebrovascular and muscular pathologies in Col4a1 mutant mice. We show efficacy of long-term 4PBA treatment in reducing the severity of intracerebral hemorrhages (ICH) in Col4a1 mutant mice aged up to 8 months. In addition, we demonstrate that maximal efficacy of 4PBA on ICH and myopathy was achieved when treatment was initiated prenatally, whereby even transient 4PBA administration had lasting benefits after being discontinued. Importantly, postnatal treatment with 4PBA also reduced ICH and skeletal myopathy severities in Col4a1 mutant mice, which has significant clinical implications for patients with COL4A1 and COL4A2 mutations.</jats:p
The Kargadoor: The Kargadoor building in Utrecht as an example of the social construct of space
No full textThis research paper focuses on a time in which contentious politics created more tensions between the youth and government, and how this conflict flourished into a social construct of new spaces. These concepts are to be explained further on in the paper. In order to provide an understanding of the relationship between contentious politics and spaces as social constructs, the case study of the Kargadoor in Utrecht will be investigated. This study emphasizes the role that Koos van Duinen, the author of this paper’s grandfather, played in this context.AR2A011Architectural History ThesisArchitecture, Urbanism and Building Science
Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation.
No full textPrecise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development
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TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage
No full textPurpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFβ) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFβ signaling ameliorated ASD, supporting a role for the TGFβ pathway in disease pathogenesis. Here, we tested whether altered TGFβ signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice.
Methods: To test the role of TGFβ signaling in glaucoma-relevant phenotypes, we genetically reduced TGFβ signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFβ ligands in Col4a1+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry.
Results: Col4a1+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFβ receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1+/G1344D mice.
Conclusions: Our results suggest that elevated TGFβ signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice
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