Gaëlle Friocourt

Gaëlle Friocourt
French Institute of Health and Medical Research | Inserm · UMR1078 - Genetics

PhD

About

65
Publications
7,372
Reads
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2,965
Citations
Citations since 2016
32 Research Items
941 Citations
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150
Introduction
We work on cortical development with a focus on ARX, a gene involved in the development of GABAergic neurons. Using mouse models and iPS technology, we study the role of this gene in cognitive and fine motor functions such as language and prehension. In another project, we are investigating the effect of cystathionine-beta synthase (CBS) overexpression in brain function. The gene dosage of this enzyme appears critical in homocystinuria and Down syndrome.
Additional affiliations
October 2011 - present
Inserm UMR1078
Position
  • Researcher
Description
  • I am currently working on two projects : the characterisation of the effect of Arx most frequent mutation and the investigation of the effect of Cystathione beta synthase (CBS) overexpression on neuronal function.
January 2006 - October 2011
Inserm U613
Position
  • PostDoc Position
Description
  • During my 2nd post-doc, I worked with foetopathologists to investigate the role of interneurons in different types of lissencephaly. In addition, with the help of Marie-Lise Quillé, we tried to characterize the targets of ARX during brain development.
May 2003 - January 2006
University College London
Position
  • PostDoc Position
Description
  • I did a first post-doc in John Parnavelas' lab in which I investigated the role of two genes involved in lissencephaly (DCX and ARX) in interneuron migration.
Education
September 1998 - July 1999
University Paris 7
Field of study
  • Human Genetics
September 1997 - July 1998
University Paris 7
Field of study
  • Cell Biology and Physiology: "Molecular and Cellular Genetics"
September 1996 - July 1999
University Paris 7
Field of study
  • Genetics

Publications

Publications (65)
Article
Full-text available
The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to...
Article
Full-text available
Type I lissencephaly, a genetic disease characterized by disorganized cortical layers and gyral abnormalities, is associated with severe cognitive impairment and epilepsy. Two genes, LIS1 and doublecortin (DCX), have been shown to be responsible for a large proportion of cases of type I lissencephaly. Both genes encode microtubule-associated protei...
Article
Full-text available
Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx exp...
Article
Full-text available
The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a du...
Article
Full-text available
The Aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise...
Article
Full-text available
CBS encodes a pyridoxal 5′-phosphate-dependent enzyme that catalyses the condensation of homocysteine and serine to form cystathionine. Due to its implication in some cancers and in the cognitive pathophysiology of Down syndrome, the identification of pharmacological inhibitors of this enzyme is urgently required. However, thus far, attempts to ide...
Article
Full-text available
Prenatal alcohol exposure is a major cause of neurobehavioral disabilities. MRI studies in humans have shown that alcohol is associated with white matter microstructural anomalies but these studies focused on myelin abnormalities only after birth. Only one of these studies evaluated oligodendrocyte lineage, but only for a short period during human...
Article
Full-text available
Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes th...
Article
Prion diseases are caused by the propagation of PrPSc, the pathological conformation of the PrPC prion protein. The molecular mechanisms underlying PrPSc propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrPSc propagation in cel...
Article
Full-text available
Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a remarkable number of cellular functions. The elevated prevalence of p53 mutations in human cancers h...
Article
Full-text available
Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density d...
Article
Full-text available
Background Hydrogen sulfide (H2S) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ -lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) are the principal enzymes responsible for its biogenesis. A recent yeast screen suggested that disulfiram (a well-known inhibitor of aldehyde dehydrogenase and a...
Data
Fig. S1. Effect of hexestrol and clomifene on mitochondrial morphology and mtDNA in galactose medium Yeast cells expressing the mitochondrial protein Arg11p fused to the fluorescent mCherry protein (Arg11p-mCherry), together with mutated Msp1p (strain msp1 P300S) were cultured at 37°C in galactose medium for 18 hours without (-) or with 20 µM hexes...
Article
Full-text available
Mitochondria continually move, fuse and divide, and these dynamics are essential for the proper function of the organelles. Indeed, the dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs as well as preserving their integrity. As a consequence, mitochondrial fusi...
Article
Full-text available
Identifying dosage-sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) shows cognitive phenotypes that need to be investigated to identify the main genetic driver. Here, we report that three copies of the cystathionine-beta-synthase gene (Cbs...
Preprint
Full-text available
Identifying dosage sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) show cognitive phenotype and needs to be investigated to identify the main genetic driver. Here, we report that, in the Dp1Yah mice, 3 copies of the Cystathionine-beta-syn...
Data
Supplementary data: Description of ARX expression in the developing human brain; Supplementary Table 1: Age and cause of death of selected autopsy cases.
Article
Bcs1p is a chaperone that is required for the incorporation of the Rieske subunit within complex III of the mitochondrial respiratory chain. Mutations in the human gene BCS1L (BCS1-like) are the most frequent nuclear mutations resulting in complex III-related pathologies. In yeast, the mimicking of some pathogenic mutations causes a respiratory def...
Poster
Objective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_...
Poster
Objective: The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons (OMIM#300215), and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in this gen...
Article
Numéro spécial Abstracts of EPNS 2017 - 12th European Paediatric Neurology Society CongressLyon, France20- 24 June 2017 12th European Paediatric Neurology Society Congress, 20 - 24 June 2017
Article
Full-text available
It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than two decades ago, depends upon the d...
Article
The Aristaless related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in embryonic development. Mutations in ARX give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. To capture the genetics and molecular disruptions that underpin the ARX-associated clinical phenotypes,...
Article
Full-text available
6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI⁺] using both PFAR-enriched mutants and site-directed methylation. We demonstrate...
Article
Full-text available
The tumor suppression activity of p53 is frequently impaired in cancers even when a wild-type copy of the gene is still present, suggesting that a dominant-negative effect is exerted by some of p53 mutants and isoforms. p63 and p73, which are related to p53, have also been reported to be subjected to a similar loss of function, suggesting that a do...
Article
Full-text available
6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI+] using both PFAR-enriched mutants and site-directed methylation. We demonstrate...
Article
Full-text available
The Epstein-Barr gammaherpesvirus (EBV) is the first oncogenic virus discovered in human. Indeed, EBV has been known for more than 50 years to be tightly associated with certain human cancers. As such, EBV has been the subject of extensive studies aiming at deciphering various aspects of its biological cycle, ranging from the regulation of its geno...
Article
Full-text available
Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible r...
Article
We report here a de novo 16q24.1 interstitial duplication in a woman with a severe phenotype consistent with mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched palate, malar hypoplasia, little subcutaneous fat and arachnodactyly. Although conventional karyotyping was found to be normal, array-CGH detected a small duplicati...
Data
Functional gene ontology categories enriched in ChIP-positive genes from N2a cells. The number and percentage of genes in each GO category are presented. The indicated P-value corresponds to modified Fisher Exact P-Value for gene-enrichment analysis (EASE score). (XLS)
Data
Example of the expression of ChIP-positive genes representative of some of the enriched biological categories in E14.5 mouse brain. Images were obtained from the public database GenePaint. The majority of genes are expressed in the developing cortex and/or ganglionic eminences, consistent with a positive or negative regulation by Arx. Ctx: cortex,...
Data
List of ChIP-positive genes showing changes of expression following Arx overexpression in N2a cells and/or in Arx knock-out mice. (XLS)
Data
ChIP-positive gene promoters identified only in N2a-transfected cells (sheet 2), only in embryonic brain (sheet 3) or in both (sheet 1). The indicated P-value for each gene corresponds to the geometrical mean of the best probe obtained from the 3 replicate experiments. Genes are listed in decreasing P-value rank order. (XLS)
Data
Functional gene ontology categories enriched in ChIP-positive genes from mouse embryonic brain. The number and percentage of genes in each GO category are presented. The indicated P-value corresponds to modified Fisher Exact P-Value for gene-enrichment analysis (EASE score). (XLS)
Data
Site-specific primers used in ChIP/QFM-PCR for the validation of Arx-bound promoter sequences. (DOC)
Article
Full-text available
Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with asso...
Article
Sterility due to bilateral destruction in utero or in early infancy resulting in congenital absence of the vas deferens is the rule in male patients with cystic fibrosis. To understand the developmental pattern of this anomaly, the microscopic morphology of the male excretory system was analyzed during development and the expression of the cystic f...
Article
Full-text available
Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3...
Article
Full-text available
During corticogenesis, neurons adopt different migration pathways to reach their final position. The precursors of pyramidal neurons migrate radially, whereas most of the GABA-containing interneurons are generated in the ventral telencephalon and migrate tangentially into the neocortex. Then, they use a radial migration mode to establish themselves...
Article
Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600...
Article
Full-text available
Genetic investigations of X-linked mental retardation have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities, but with associated features of dystonia and epi...
Article
Full-text available
The cystic fibrosis transmembrane conductance regulator (CFTR) functions as a cAMP-activated chloride channel, which is regulated by protein-protein interactions. The extent to which CFTR is regulated by these interactions remains unknown. Annexin V is overexpressed in cystic fibrosis (CF), and given the functional properties of annexin V and CFTR...
Article
The ARX protein (encoded by the aristaless-related homeobox gene) is a member of the paired class of homeoproteins. More precisely, it is a member of the Aristaless subclass of proteins with a glutamine residue (Q) at the critical position 50 of the homeodomain (Q50). Through identification of diverse inherited or de novo mutations, genetic investi...
Article
Doublecortin (DCX) is a microtubule-associated protein involved in neuronal migration, which causes X-linked lissencephaly and subcortical laminar heterotopia (SCLH) when mutated. Here we show that DCX interacts with the ubiquitin-specific protease Drosophila fat facets related on X chromosome (DFFRX). This interaction was confirmed by targeted mut...
Article
Recent human genetics approaches identified the Aristaless-related homeobox (ARX) gene as the causative gene in X-linked infantile spasms, Partington syndrome, and non-syndromic mental retardation as well as in forms of lissencephaly with abnormal genitalia. The ARX predicted protein belongs to a large family of homeoproteins and is characterised b...
Article
Full-text available
Type I lissencephaly is a cortical malformation disorder characterized by disorganized cortical layers and gyral abnormalities and associated with severe cognitive impairment and epilepsy. The exact pathophysiological mechanisms underlying the epilepsy and mental retardation in this and related disorders remain unknown. Two genes, LIS1 and doubleco...
Article
Full-text available
Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the e...
Article
Full-text available
Caspase-8 is the prototypic initiator of the death domain receptor pathway of apoptosis. Here, we report that caspase-8 not only triggers and amplifies the apoptotic process at cytoplasmic sites but can also act as an executioner at nuclear levels. In a murine model of acute ischemia, caspase-8 is relocated into the nucleus of apoptotic neurons, wh...
Article
Full-text available
Investigation of a critical region for an X-linked mental retardation (XLMR) locus led us to identify a novel Aristaless related homeobox gene (ARX ). Inherited and de novo ARX mutations, including missense mutations and in frame duplications/insertions leading to expansions of polyalanine tracts in ARX, were found in nine familial and one sporadic...
Article
Doublecortin is a microtubule-associated protein required for normal corticogenesis in the developing brain. We carried out a yeast two-hybrid screen to identify interacting proteins. One of the isolated clones encodes the mu1 subunit of the adaptor complex AP-1 involved in clathrin-dependent protein sorting. We found that Doublecortin also interac...
Article
Cardiotrophin-1 (CT-1) is a potent neurotrophic factor for motoneurons but its clinical use in motor neuron diseases is precluded by side effects on the heart and liver. We explored the possibility of targeting CT-1 to neurons by coupling with the tetanus toxin fragment TTC. Genetic fusion proteins between CT-1 or GFP and TTC were produced in Esche...
Article
Full-text available
X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous. They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning,...
Article
Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia. Here, we show that Doublecortin is expressed in the brain throughout the period of corticogenesis in migrating and differentiating neurons. Immunohistochemical studies show its localization in the soma and leadi...

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Projects

Projects (7)
Project
We developed a new cellular model to identify molecules interfering with the effects of CBS overexpression, which appears to contribute to the cognitive defects of patients with Down syndrome.
Project
Identify new therapeutics for prion-like diseases and better understand the molecular aspects of the propagation of the pathological conformation of prion and prionoid proteins