Jean-Luc Vilotte

French National Institute for Agricultural Research, Lutetia Parisorum, Île-de-France, France

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Publications (49)203.74 Total impact

  • Placenta 09/2014; 35(9):A78. · 3.29 Impact Factor
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    ABSTRACT: Based on its developmental pattern of expression, early studies suggested the implication of the mammalian Prion protein PrP, a glycosylphosphatidylinositol-anchored ubiquitously expressed and evolutionary conserved glycoprotein encoded by the Prnp gene, in early embryogenesis. However, gene invalidation in several species did not result in obvious developmental abnormalities and it was only recently that it was associated in mice with intra-uterine growth retardation and placental dysfunction. A proposed explanation for this lack of easily detectable developmental-related phenotype is the existence in the genome of one or more gene (s) able to compensate for the absence of PrP. Indeed, two other members of the Prnp gene family have been recently described, Doppel and Shadoo, and the consequences of their invalidation alongside that of PrP tested in mice. No embryonic defect was observed in mice depleted for Doppel and PrP. Interestingly, the co-invalidation of PrP and Shadoo in two independent studies led to apparently conflicting observations, with no apparent consequences in one report and the observation of a developmental defect of the ectoplacental cone that leads to early embryonic lethality in the other. This short review aims at summarizing these recent, apparently conflicting data highlighting the related biological questions and associated implications in terms of animal and human health.
    Frontiers in Cell and Developmental Biology 08/2014; 2:35.
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    ABSTRACT: The dietary exposure of the human population to the prions responsible for the bovine spongiform encephalopathy (BSE) epizooty has led to the emergence of variant Creutzfeldt-Jakob disease (vCJD). This fatal, untreatable neurodegenerative disorder is a growing public health concern because the prevalence of the infection seems much greater than the disease incidence and because secondary transmission of vCJD by blood transfusion or use of blood products has occurred. A current limitation in variant CJD risk assessment purposes is the lack of quantitative information on the infectivity of contaminated tissues. To these aims, we tested the potential of a transgenic mouse line overexpressing human PrP, which was previously reported to propagate vCJD prions. Endpoint titration of vCJD infectivity in different tissues was evaluated by two different methods: i) the "classical" bioassay, based on the appearance of clinical symptoms and the detection of pathological prion protein in tissues of the inoculated mouse, ii) a shortened bioassay based on the detection of the protein in the mouse spleen at defined time points. Both methods proved equally sensitive in quantifying infectivity, even after very low dose inoculation of infected material, but the time time-schedule was shortened from ∼2.5-year to ∼1-year with the spleen bioassay. Compared to the 'gold-standard' RIII model routinely used for endpoint titration of vCJD/BSE prions, either method improved the sensitivity by >2 orders of magnitude and allowed re-evaluating the infectious titre of spleen from a vCJD individual at disease end stage to >1000-fold higher values.
    Journal of Virology 05/2014; · 4.65 Impact Factor
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    ABSTRACT: Aims: Storkhead Box 1 (STOX1) is a winged-helix transcription factor implicated in the genetic forms of a high-prevalence human gestational disease, preeclampsia. STOX1 overexpression confers preeclampsia-like transcriptomic features to trophoblastic cell lines, and preeclampsia symptoms to pregnant mice. The aim of this work was to evaluate the impact of STOX1 on free radical equilibrium and mitochondrial function, in vitro and in vivo. Results: Transcriptome analysis of STOX1-transgenic versus non-transgenic placentas at 16.5 days of gestation revealed alterations of mitochondria-related pathways. Placentas overexpressing STOX1 displayed altered mitochondrial mass and were severely biased towards protein nitration, indicating nitroso-redox imbalance in vivo. Trophoblast cells overexpressing STOX1 displayed an increased mitochondrial activity at 20% O2 and in hypoxia, despite a reduction of the mitochondrial mass in this situation. STOX1 overexpression is therefore associated to hyperactive mitochondria leading to increased free radical production. Moreover, nitric oxide (NO) production pathways were activated, resulting in peroxynitrite formation. At low oxygen pressure, STOX1 overexpression in the placenta as well as in a trophoblast cell line, switched the free radical balance from Reactive Oxygen Species (ROS) to Reactive Nitrogen Species (RNS). Innovation: In preeclamptic placentas, NO interacts with ROS to generate peroxynitrite and nitrated proteins as end products. This process will deprive the maternal organism of NO, a crucial vasodilator molecule. Conclusion: Our data posit STOX1 as a genetic switch in the ROS/RNS balance and suggest an explanation for elevated blood pressure in preeclampsia.
    Antioxidants & Redox Signaling 04/2014; · 8.20 Impact Factor
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    ABSTRACT: The cellular prion protein PrP(C) was initially discovered as the normal counterpart of the pathological scrapie prion protein PrP(Sc), the main component of the infectious agent of Transmissible Spongiform Encephalopathies. While clues as to the physiological function of this ubiquitous protein were greatly anticipated from the development of knockout animals, PrP-null mice turned out to be viable and to develop without major phenotypic abnormalities. Notwithstanding, the discovery that hematopoietic stem cells from PrP-null mice have impaired long-term repopulating potential has set the stage for investigating into the role of PrP(C) in stem cell biology. A wealth of data have now exemplified that PrP(C) is expressed in distinct types of stem cells and regulates their self-renewal as well as their differentiation potential. A role for PrP(C) in the fate restriction of embryonic stem cells has further been proposed. Paralleling these observations, an overexpression of PrP(C) has been documented in various types of tumors. In line with the contribution of PrP(C) to stemness and to the proliferation of cancer cells, PrP(C) was recently found to be enriched in subpopulations of tumor-initiating cells. In the present review, we summarize the current knowledge of the role played by PrP(C) in stem cell biology and discuss how the subversion of its function may contribute to cancer progression.
    Frontiers in Cell and Developmental Biology 01/2014; 2:55.
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    ABSTRACT: The deletion of the cellular form of the prion protein (PrP(C)) in mouse, goat, and cattle has no drastic phenotypic consequence. This stands in apparent contradiction with PrP(C) quasi-ubiquitous expression and conserved primary and tertiary structures in mammals, and its pivotal role in neurodegenerative diseases such as prion and Alzheimer's diseases. In zebrafish embryos, depletion of PrP ortholog leads to a severe loss-of-function phenotype. This raises the question of a potential role of PrP(C) in the development of all vertebrates. This view is further supported by the early expression of the PrP(C) encoding gene (Prnp) in many tissues of the mouse embryo, the transient disruption of a broad number of cellular pathways in early Prnp(-/-) mouse embryos, and a growing body of evidence for PrP(C) involvement in the regulation of cell proliferation and differentiation in various types of mammalian stem cells and progenitors. Finally, several studies in both zebrafish embryos and in mammalian cells and tissues in formation support a role for PrP(C) in cell adhesion, extra-cellular matrix interactions and cytoskeleton. In this review, we summarize and compare the different models used to decipher PrP(C) functions at early developmental stages during embryo- and organo-genesis and discuss their relevance.
    Frontiers in Cell and Developmental Biology 01/2014; 2:58.
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    ABSTRACT: In naturally acquired transmissible spongiform encephalopathies, the pathogenic agents or prions spread from the sites of initial peripheral uptake or replication to the brain where they cause progressive and fatal neurodegeneration. Routing via the peripheral nervous system is considered as one of the main pathways to attain the central nervous system. Replication of prions in Schwann cells is viewed as a potentially important parameter for efficient prion spread along nerves. Here we used a Cre-loxP mouse transgenetic approach to disrupt PrPC specifically in myelinating Schwann cells. Despite the use of infection routes targeting highly myelinated nerves, there was no alteration in mouse prion pathogenesis, suggesting that conversion-dependent, centripetal spread of prions does not crucially rely on PrPC expressed by myelinating Schwann cells.
    Journal of General Virology 02/2013; · 3.53 Impact Factor
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    ABSTRACT: Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.
    Hypertension 01/2013; · 7.63 Impact Factor
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    ABSTRACT: Although the pivotal implication of the host-encoded Prion protein, PrP, in the neuropathology of transmissible spongiform encephalopathy is known for decades, its biological role remains mostly elusive. Genetic inactivation is one way to assess such issue but, so far, PrP-knockout mice did not help much. However, recent reports involving (1) further studies of these mice during embryogenesis, (2) knockdown experiments in Zebrafish and (3) knockdown of Shadoo, a protein with PrP-like functional domains, in PrP-knockout mice, all suggested a role of the Prion protein family in early embryogenesis. This view is challenged by the recent report that PrP/Shadoo knockout mice are healthy and fertile. Although puzzling, these apparently contradictory data may on the contrary help at deciphering the Prion protein family role through focusing scientific attention outside the central nervous system and by helping the identification of other loci involved in the genetic robustness associated with PrP.
    Prion 11/2012; 7(2). · 1.97 Impact Factor
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    ABSTRACT: BACKGROUND: Myostatin, a member of the TGFbeta superfamily, is well known as a potent and specific negative regulator of muscle growth. Targeting the myostatin signalling pathway may offer promising therapeutic strategies for the treatment of muscle-wasting disorders. In the last decade, various myostatin-binding proteins have been identified to be able to inhibit myostatin activity. One of these is GASP1 (Growth and Differentiation Factor-Associated Serum Protein-1), a protein containing a follistatin domain as well as multiple domains associated with protease inhibitors. Despite in vitro data, remarkably little is known about in vivo functions of Gasp1. To further address the role of GASP1 during mouse development and in adulthood, we generated a gain-of-function transgenic mouse model that overexpresses Gasp1 under transcriptional control of the human cytomegalovirus immediate-early promoter/enhancer. RESULTS: Overexpression of Gasp1 led to an increase in muscle mass observed not before day 15 of postnatal life. The surGasp1 transgenic mice did not display any other gross abnormality. Histological and morphometric analysis of surGasp1 rectus femoris muscles revealed an increase in myofiber size without a corresponding increase in myofiber number. Fiber-type distribution was unaltered. Interestingly, we do not detect a change in total fat mass and lean mass. These results differ from those for myostatin knockout mice, transgenic mice overexpressing the myostatin propeptide or follistatin which exhibit both muscle hypertrophy and hyperplasia, and show minimal fat deposition. CONCLUSIONS: Altogether, our data give new insight into the in vivo functions of Gasp1. As an extracellular regulatory factor in the myostatin signalling pathway, additional studies on GASP1 and its homolog GASP2 are required to elucidate the crosstalk between the different intrinsic inhibitors of the myostatin.
    BMC Genomics 10/2012; 13(1):541. · 4.04 Impact Factor
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    ABSTRACT: MicroRNA (miRNA) are negative regulators of gene expression, capable of exerting pronounced influences upon the translation and stability of mRNA. They are potential regulators of normal mammary gland development and of the maintenance of mammary epithelial progenitor cells. This study was undertaken to determine the role of miR-30b on the establishment of a functional mouse mammary gland. miR-30b is a member of the miR-30 family, composed of 6 miRNA that are highly conserved in vertebrates. It has been suggested to play a role in the differentiation of several cell types. The expression of miR-30b was found to be regulated during mammary gland development. Transgenic mice overexpressing miR-30b in mammary epithelial cells were used to investigate its role. During lactation, mammary histological analysis of the transgenic mice showed a reduction in the size of alveolar lumen, a defect of the lipid droplets and a growth defect of pups fed by transgenic females. Moreover some mammary epithelial differentiated structures persisted during involution, suggesting a delay in the process. The genes whose expression was affected by the overexpression of miR-30b were characterized by microarray analysis. Our data suggests that miR-30b is important for the biology of the mammary gland and demonstrates that the deregulation of only one miRNA could affect lactation and involution.
    PLoS ONE 09/2012; 7(9):e45727. · 3.53 Impact Factor
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    ABSTRACT: The potential requirement of either the Prion or Shadoo protein for early mouse embryogenesis was recently suggested. However, the current data did not allow to precise the developmental process that was affected in the absence of both proteins and that led to the observed early lethal phenotype. In the present study, using various Prnp transgenic mouse lines and lentiviral vectors expressing shRNAs that target the Shadoo-encoding mRNA, we further demonstrate the specific requirement of at least one of these two PrP-related proteins at early developmental stages. Histological analysis reveals developmental defect of the ectoplacental cone and important hemorrhage surrounding the Prnp-knockout-Sprn-knockdown E7.5 embryos. By restricting the RNA interference to the trophoblastic cell lineages, the observed lethal phenotype could be attributed to the sole role of these proteins in this trophectoderm-derived compartment. RNAseq analysis performed on early embryos of various Prnp and Sprn genotypes indicated that the simultaneous down-regulation of these two proteins affects cell-adhesion and inflammatory pathways as well as the expression of ectoplacental-specific genes. Overall, our data provide biological clues in favor of a crucial and complementary embryonic role of the prion protein family in Eutherians and emphasizes the need to further evaluate its implication in normal and pathological human placenta biology.
    PLoS ONE 07/2012; 7(7):e41959. · 3.53 Impact Factor
  • Vincent Béringue, Jean-Luc Vilotte, Hubert Laude
    Medecine sciences: M/S 06/2012; 28(6-7):565-8. · 0.52 Impact Factor
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    ABSTRACT: Compared to experiments involving pigs, cows and/or sheep, transgenesis applied to goats is probably less advertised. However, recent successes and increasing amount of dedicated research make this species of special interest for ongoing biological and physiological questions on genome engineering in large animals. This short review aims at highlighting the current applications and limitations of the goat genome manipulation.
    Transgenic Research 04/2012; 21(6). · 2.28 Impact Factor
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    ABSTRACT: Prions are infectious pathogens essentially composed of PrP(Sc), an abnormally folded form of the host-encoded prion protein PrP(C). Constrained steric interactions between PrP(Sc) and PrP(C) are thought to provide prions with species specificity and to control cross-species transmission into other host populations, including humans. We compared the ability of brain and lymphoid tissues from ovine and human PrP transgenic mice to replicate foreign, inefficiently transmitted prions. Lymphoid tissue was consistently more permissive than the brain to prions such as those causing chronic wasting disease and bovine spongiform encephalopathy. Furthermore, when the transmission barrier was overcome through strain shifting in the brain, a distinct agent propagated in the spleen, which retained the ability to infect the original host. Thus, prion cross-species transmission efficacy can exhibit a marked tissue dependence.
    Science 01/2012; 335(6067):472-5. · 31.48 Impact Factor
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    ABSTRACT: The prion-like protein Shadoo has been suggested to compensate for the lack of PrP in Prnp-knockout mice, explaining their lack of extreme phenotype. In adult mice, both PrP and Shadoo have shown overlapping expression patterns and shared functions. Their expression in the mouse embryo has also been suggested to be complementary, as invalidation of both genes results in embryonic lethality. The developmental expression profile of PrP has been described from post-implantation stages up until birth. However the spatial expression pattern of Shadoo in the developing mouse embryo is not known. We previously described the expression profile of the prion-like protein Shadoo in adult mice using Sprn reporter mice (Sprn-GFP and Sprn-LacZ). Here we used these mice to describe the developmental expression of Shadoo between 10.5 and 14.5 dpc. The observed pattern in specific embryonic cell lineages and in extra-embryonic tissues is consistent with the previously reported phenotype resulting from its knockdown.
    Biochemical and Biophysical Research Communications 11/2011; 416(1-2):184-7. · 2.28 Impact Factor
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    ABSTRACT: The protein Shadoo (Sho) is a paralogue of prion protein, and encoded by the gene Sprn. Like prion protein it is primarily expressed in central nervous system, and has been shown to have a similar expression pattern in certain regions of the brain. We have generated reporter mice carrying a transgene encompassing the Sprn promoter, exon 1, intron 1 and the 5'-end of exon 2 driving expression of either the LacZ or GFP reporter gene to study the expression profile of Shadoo in mice. Expression of the reporter genes was analysed in brains of these transgenic mice and was shown to mimic that of the endogenous gene expression, previously described by Watts et al. [1]. Consequently, the Sprn-LacZ mice were used to study the spatial expression of Sho in other tissues of the adult mouse. Several tissues were collected and stained for β-gal activity, including the thymus, heart, lung, liver, kidney, spleen, intestine, muscle, and gonads. From this array of tissues, the transgene was consistently expressed only in specific cell types of the testicle and ovary, suggesting a role for Shadoo in fertility and reproduction. These mice may serve as a useful tool in deciphering the regulation of the prion-like gene Sprn and thus, indirectly, of the Shadoo protein.
    Biochemical and Biophysical Research Communications 08/2011; 412(4):752-6. · 2.28 Impact Factor
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    ABSTRACT: The biological function of the Prion protein remains largely unknown but recent data revealed its implication in early zebrafish and mammalian embryogenesis. To gain further insight into its biological function, comparative transcriptomic analysis between FVB/N and FVB/N Prnp knockout mice was performed at early embryonic stages. RNAseq analysis revealed the differential expression of 73 and 263 genes at E6.5 and E7.5, respectively. The related metabolic pathways identified in this analysis partially overlap with those described in PrP1 and PrP2 knockdown zebrafish embryos and prion-infected mammalian brains and emphasize a potentially important role for the PrP family genes in early developmental processes.
    PLoS ONE 08/2011; 6(8):e23253. · 3.53 Impact Factor
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    ABSTRACT: The physiological function of the prion protein remains largely elusive while its key role in prion infection has been expansively documented. To potentially assess this conundrum, we performed a comparative transcriptomic analysis of the brain of wild-type mice with that of transgenic mice invalidated at this locus either at the zygotic or at the adult stages. Only subtle transcriptomic differences resulting from the Prnp knockout could be evidenced, beside Prnp itself, in the analyzed adult brains following microarray analysis of 24 109 mouse genes and QPCR assessment of some of the putatively marginally modulated loci. When performed at the adult stage, neuronal Prnp disruption appeared to sequentially induce a response to an oxidative stress and a remodeling of the nervous system. However, these events involved only a limited number of genes, expression levels of which were only slightly modified and not always confirmed by RT-qPCR. If not, the qPCR obtained data suggested even less pronounced differences. These results suggest that the physiological function of PrP is redundant at the adult stage or important for only a small subset of the brain cell population under classical breeding conditions. Following its early reported embryonic developmental regulation, this lack of response could also imply that PrP has a more detrimental role during mouse embryogenesis and that potential transient compensatory mechanisms have to be searched for at the time this locus becomes transcriptionally activated.
    BMC Genomics 01/2010; 11:448. · 4.04 Impact Factor
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    ABSTRACT: Non-mouse mammalian transgenesis is limited by its overall inefficiency and technical hurdles. Recent years have seen the emergence of two approaches that are applicable to most mammals. The first, based on lentivirus vectors, allows efficient generation of transgenic founders, most of them expressing the transgene. The second, recently applied to produce transgenic fish and mammals, takes advantage of the design of specific 'DNA-scissors' for efficient introduction of subtle mutations in potentially any region of the genome. This review focuses on the potential of this latter technology to modify mammalian genomes without the need to apply challenging and less-efficient protocols. We highlight the complementary aims of these new approaches and the as-yet-unexplored possibilities offered by their combination.
    Trends in Biotechnology 12/2009; 28(3):134-41. · 10.04 Impact Factor

Publication Stats

862 Citations
203.74 Total Impact Points

Institutions

  • 2002–2014
    • French National Institute for Agricultural Research
      • • Génétique Animale et Biologie Intégrative (GABI)
      • • Génomique et Physiologie de la Lactation
      • • Virologie et Immunologie Moléculaires (VIM)
      • • Département de Génétique Animale
      Lutetia Parisorum, Île-de-France, France