Marc Lombès

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (132)559.43 Total impact

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    ABSTRACT: The mineralocorticoid receptor (MR) mediates the Na(+)-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of the tristetraprolin/ZFP36 family, and thereby, decreases MR expression in renal KC3AC1 cells. The 3'-untranslated regions (3'-UTRs) of human and mouse MR mRNA, containing several highly conserved adenylate/uridylate-rich elements (AREs), were cloned downstream of a reporter gene. Luciferase activities of full-length or truncated MR Luc-3'-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of ARE-containing transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 3'-UTR, to which Tis11b must bind for destabilizing activity. Coimmunoprecipitation experiments suggested that endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, and Tis11b knockdown prevented hypertonicity-elicited repression of MR. Moreover, hypertonicity blunted aldosterone-stimulated expression of glucocorticoid-induced leucine-zipper protein and the α-subunit of the epithelial Na(+) channel, supporting impaired MR signaling. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration, or high-Na(+) diet increased renal Tis11b and decreased MR expression, particularly in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncovered a mechanism by which renal MR expression is regulated through mRNA turnover, a post-transcriptional control that seems physiologically relevant.
    Journal of the American Society of Nephrology 04/2014; · 8.99 Impact Factor
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    ABSTRACT: Context: Sotos syndrome is a rare genetic disorder with a distinct phenotypic spectrum including overgrowth and learning difficulties. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. Objective: We strived to elucidate the evanescent nature of the observed hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4 - which are both associated with FGF23-mediated mineral homeostasis - in the developing human kidney. Design: RT-qPCR and immunohistochemical analyses were used on archival human kidney samples to investigate expression of the FGFR signaling pathway during renal development. Results: We demonstrated that renal gene and protein expression of both FGFRs increased during fetal development between the gestational ages (GA) of 14-40 weeks. Yet, FGFR4 expression increased more rapidly as compared to FGFR3 (slope: 0.047 vs. 0.0075, p = 0.0018). Moreover, gene and protein expression of the essential FGFR co-receptor, Klotho, also increased with a significant positive correlation between FGFR and Klotho mRNA expression during renal development. Interestingly, we found that perinatal FGFR4 expression (GA 38-40 weeks) was 7-fold higher as compared to FGFR3 (p=0.0035), while in adult kidney tissues, FGFR4 gene expression level was more than 2-fold lower compared to FGFR3 (p=0.0029), thus identifying a molecular developmental switch of FGFR isoforms. Conclusion: We propose that the heterozygous FGFR4 deletion, as observed in the Sotos syndrome patient, leads to a compromised FGF23 signaling during infancy accounting for transient hypercalcemia. These findings represent a novel and intriguing view on FGF23-mediated calcium homeostasis.
    The Journal of clinical endocrinology and metabolism 03/2014; · 6.50 Impact Factor
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    ABSTRACT: Mature Sertoli cells (SC) are critical mediators of androgen regulation of spermatogenesis, via the androgen receptor (AR) signaling. Available immortalized SC lines loose AR expression or androgen responsiveness, hampering the study of endogenous AR regulation in SC. We have established and characterized a novel clonal mouse immortalized SC line, ST38c. These cells express some SC specific genes (sox9, wt1, tjp1, clu, abp, inhbb), but not fshr, yet more importantly, maintain substantial expression of endogenous AR as determined by PCR, immunocytochemistry, testosterone binding assays and Western blots. Microarrays allowed identification of some (146) but not all (rhox5, spinlw1), androgen-dependent, SC expressed target genes. Quantitative Real-Time PCR validated regulation of five up-regulated and two down-regulated genes. We show that AR undergoes androgen-dependent transcriptional activation as well as agonist-dependent posttranslational stabilization in ST38c cells. This cell line constitutes a useful experimental tool for future investigations on the molecular and cellular mechanisms of androgen receptor signaling in SC function.
    Molecular and Cellular Endocrinology 01/2014; · 4.04 Impact Factor
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    ABSTRACT: The mineralocorticoid receptor (MR) exerts pro-adipogenic and anti-thermogenic effects in vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high fat diet (HFD) for 16 wks. Tg mice had a lower body weight gain than WT animals, and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease of fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared to WT animals. Quantitative RT-PCR studies revealed decreased expression of PPARγ2, a master adipogenic gene, and of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other non-adipocyte factors might compromise AT development. While AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by directly controlling adipocyte differentiation processes but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders.
    AJP Endocrinology and Metabolism 11/2013; · 4.51 Impact Factor
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    ABSTRACT: Several autoimmune diseases (AID), including primary Sjögren's syndrome (pSS), are associated with an increased risk of lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling NF-kB activation, have been associated with several AID. Somatic mutations of TNFAIP3 have been observed in the MALT lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 pSS patients, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk of pSS complicated by lymphoma (OR= 3.36 [95%CI 1.34-8.42] and OR=3.26 [95%CI 1.31-8.12], p=0.011, versus controls and pSS patients without lymphoma, respectively). Twelve of the 20 (60%) patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20, 6 in germline DNA, 5 in lymphoma DNA and 1 in both. The frequency was even higher (77%) among pSS patients with MALT lymphoma. Some of these variants showed impaired control of NF-kB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.
    Blood 10/2013; · 9.06 Impact Factor
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    ABSTRACT: A better understanding of molecular mechanisms responsible for tumorigenesis has allowed the development of targeted drugs designed to improve the outcome of cancer. In endocrine tumors, several molecules have demonstrated efficacy in terms of progression free survival during phase III trials such as vandetanib and cabozantinib in medullary thyroid carcinoma, sorafenib in differentiated thyroid carcinoma and everolimus or sunitinib for pancreatic neuroendocrine tumors. Rare cancer network has allowed ongoing phase III trials in malignant pheochromocytoma and adrenocortical carcinoma. However, to date no specific predictive biomarker has yet been identified for a personalized cancer medicine. We review recent advances in endocrine oncology concerning molecular targets identification, targeted therapies and predictive or prognostic markers.
    Annales d Endocrinologie 10/2013; 74 Suppl 1:S13-22. · 1.02 Impact Factor
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    ABSTRACT: Prolactin (PRL) and placental lactogens stimulate beta cell replication and insulin production in pancreatic islets and insulinoma cells through binding to the PRL receptor (PRLR). However, the contribution of PRLR signaling to beta cell ontogeny and function in perinatal life and the effects of the lactogens on adaptive islet growth are poorly understood. We provide evidence that expansion of beta cell mass during both embryogenesis and the postnatal period is impaired in the PRLR-/- mouse model. PRLR-/- newborns display a 30% reduction of beta cell mass, consistent with reduced proliferation index at E18.5. PRL stimulates leucine incorporation and S6 kinase phosphorylation in INS-1 cells, supporting a role for beta cell mTOR signaling in PRL action. Interestingly, a defect in the development of acini is also observed in absence of PRLR signaling, with a sharp decline in cellular size in both endocrine and exocrine compartments. Of note, a decrease in levels of IGF-2, a PRL target, in the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes, is associated with lack of PRL-mediated beta cell proliferation in embryonic pancreatic buds. Reduced pancreatic IGF2 expression in both rat and mouse models suggests that this factor may constitute a molecular link between PRL signaling and cell ontogenesis. Together, these results provide evidence that PRL signaling is essential for pancreas ontogenesis during the critical perinatal window responsible for establishing functional beta cell reserve.
    AJP Endocrinology and Metabolism 09/2013; · 4.51 Impact Factor
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    ABSTRACT: Context:Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and scant treatment options. In ACC, no personalized approach has emerged but no extensive molecular screening has been performed to date.Objective:The objective of the study was to evaluate the presence of a large number of potentially targetable molecular events in a large cohort of advanced ACC.Design, Setting, and Participants:We used hot spot gene sequencing (Ion Torrent, 40 patients) and comparative genomic hybridization (CGH; 28 patients; a subset of the entire cohort) in adult stage III-IV ACC samples to screen for mutations and copy number abnormalities of potential interest for therapeutic use in 46 and 130 genes, respectively.Results:At least one copy number alteration or mutation was found in 19 patients (47.5%). The most frequent mutations were detected on TP53, ATM, and CTNNB1 [6 of 40 (15%), 5 of 40 (12.5%), and 4 of 40 (10%), respectively]. The most frequent copy number alterations identified were: amplification of the CDK4 oncogene (5 of 28; 17.9%) and deletion of the CDKN2A (4 of 28; 14.3%) and CDKN2B (3 of 28; 10.7%) tumor suppressor genes. Amplifications of FGFR1, FGF9, or FRS2 were discovered in three subjects (10.7%). Associated alterations were: deletions of CDKN2A, CDKN2B with ATM mutations, and TP53 mutations with CTNNB1 mutations.Conclusions:No simple targetable molecular event emerged. Drugs targeting the cell cycle could be the most relevant new therapeutic approach for patients with advanced ACC. Inhibitors of the fibroblast growth factor receptor pathway could also be a therapeutic option in a subset of patients, whereas other targeted therapies should be considered on a case-by-case basis.
    The Journal of clinical endocrinology and metabolism 08/2013; · 6.50 Impact Factor
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    ABSTRACT: Currently available progesterone (P4) receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent x-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR. We report here the synthesis and characterization of a novel class of PR antagonists (APRn) designed from such studies. The lead molecule, the homosteroid APR19, displays in vivo endometrial anti-P4 activity. APR19 inhibits P4-induced PR recruitment and transactivation from synthetic and endogenous gene promoters. Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors and is devoid of any partial agonist activity on PR target gene transcription. Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either steroid receptor coactivators 1 and 2 (SRC1 and SCR2) or nuclear receptor corepressor (NcoR) and silencing mediator of retinoid acid and thyroid hormone receptor (SMRT), in contrast to RU486-PR complexes. APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics. In silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to P4, APR19 does not establish stabilizing hydrogen bonds with the ligandbinding cavity, resulting in an unstable ligand-receptor complex. Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins that inactivate PR by a passive mechanism. These specific PR antagonists opennew perspectives for long-term hormonal therapy.
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    ABSTRACT: Androgen receptor (AR) is essential for testicular physiology and spermatogenesis. SRC-2 and HBO1 are two AR coregulators yet their expression and roles in human testis are unknown. For the first time, we studied by immunohistochemistry and RT-PCR, the expression and distribution of these two coregulators during human testicular ontogenesis, in patients with altered AR signaling (Androgen insensitivity syndrome, AIS) and evaluated the functional impact of SRC-2 and HBO1 on AR signaling in a Sertoli cell context. SRC-2 was present in Sertoli cells at all developmental stages. HBO1 was barely or focally detected in the fetal testis yet its expression, in Sertoli and germ cells, drastically increased postnatally from early infancy to adulthood. In transient co-transfection studies we showed that SRC-2 induced, while HBO1 inhibited AR-mediated transactivation of reporter constructs in murine Sertoli SMAT1 cells. HBO1, but not SRC-2, expression was reduced in testes of patients with AIS compared to normal testes.
    Molecular and Cellular Endocrinology 05/2013; · 4.04 Impact Factor
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    [show abstract] [hide abstract]
    ABSTRACT: Currently available progesterone receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent X-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR. We report here the synthesis and characterization of a novel class of PR antagonists designed from such studies. The lead molecule, the homosteroid APR19, displays in vivo endometrial antiprogesterone activity. APR19 inhibits progesterone-induced PR recruitment and transactivation from synthetic and endogenous gene promoters. Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors, and is devoid of any partial agonist activity on PR target gene transcription. Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either transcriptional coactivators (SRC1, SCR2) or corepressors (NCoR, SMRT), in contrast to RU486-PR complexes. APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics. In-silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to progesterone, APR19 does not establish stabilizing hydrogen bonds with the ligand binding cavity, resulting in an unstable ligand-receptor complex. Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins which inactivate PR by a passive mechanism. These specific PR antagonists open new perspectives for long term hormonal therapy.
    Molecular Endocrinology 04/2013; · 4.75 Impact Factor
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    ABSTRACT: Context:Primary ovarian insufficiency (POI) is a disorder affecting approximately 1% of women under the age of 40 years. NR5A1 (SF-1) mutations have been recently reported in association with POI.Objective:Our objective was to evaluate the frequency and functional impact of NR5A1 variants in POI.Patients and Methods:One hundred eighty patients diagnosed with idiopathic POI were screened for NR5A1 mutations and functional analysis was performed for the identified variants. The DNA-binding capacity of the variants was evaluated by means of EMSA, while their transcriptional activity was assessed using luciferase reporter assays.Results:Sequencing the NR5A1 gene revealed 4 missense variants in 3 patients. These patients were aged 20, 25, and 33 years at diagnosis and presented with secondary amenorrhea. None of them presented a syndromic form, although 2 had a familial history of POI. The functional analysis carried out for these missense variants showed no significant difference in DNA binding capacity or in transcriptional activity compared to wild-type NR5A1.Conclusions:Our study in a large cohort of patients with POI showed the prevalence of NR5A1 mutations to be low (1.6%, upper 95% confidence interval 3.5%). Moreover, no functional impact was observed. Overall, in contrast with the initial report, our results exclude NR5A1 mutations as a major genetic cause of POI.
    The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
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    ABSTRACT: Progesterone receptor (PR) and progestins are known to impact mammary tumorigenesis, however the relative contribution of PRA and PRB isoforms in cancer cell migration remains elusive. By using a biinducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the impact of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(-) cells. R5020 progestin limited this effect that was counteracted by antagonist RU486. Importantly, PRA coexpression potentiated PRB-mediated migration whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration such as urokinase plasminogen activator (uPA), its inhibitor PAI-1, uPA receptor (uPAR) and β1-integrin, known to impact Focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation, and colocalized with activated FAK in cell protrusions. Since PRB as well as PRA coimmunoprecipitated with FAK, both isoforms may interact with FAK complexes depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such impact of PRB/PRA expression on FAK signaling may thus affect adhesion/motility underscoring the implication of PR isoforms in breast cancer invasivity and metastatic evolution with underlain therapeutic outcomes.
    Molecular biology of the cell 03/2013; · 5.98 Impact Factor
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    ABSTRACT: Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1 regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the interest of GH therapy in these conditions.
    Endocrine reviews 01/2013; · 19.76 Impact Factor
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    ABSTRACT: A better understanding of molecular mechanisms responsible for tumorigenesis has allowed the development of targeted drugs designed to improve the outcome of cancer. In endocrine tumors, several molecules have demonstrated efficacy in terms of progression free survival during phase III trials such as vandetanib and cabozantinib in medullary thyroid carcinoma, sorafenib in differentiated thyroid carcinoma and everolimus or sunitinib for pancreatic neuroendocrine tumors. Rare cancer network has allowed ongoing phase III trials in malignant pheochromocytoma and adrenocortical carcinoma. However, to date no specific predictive biomarker has yet been identified for a personalized cancer medicine. We review recent advances in endocrine oncology concerning molecular targets identification, targeted therapies and predictive or prognostic markers.
    Annales d'Endocrinologie. 01/2013; 74:S13–S22.
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    ABSTRACT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation. An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy. We show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH.
    PLoS ONE 01/2013; 8(1):e53896. · 3.73 Impact Factor
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    ABSTRACT: Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.
    Endocrine Related Cancer 01/2013; 20(3):371-381. · 5.26 Impact Factor
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    ABSTRACT: Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.
    PLoS ONE 01/2013; 8(7):e69616. · 3.73 Impact Factor
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    ABSTRACT: The mineralocorticoid signaling pathway has gained interest over the past few years, considering not only its implication in numerous pathologies but also its emerging role in physiological processes during kidney, brain, heart and lung development. This review aims at describing the setting and regulation of aldosterone biosynthesis and the expression of the mineralocorticoid receptor (MR), a nuclear receptor mediating aldosterone action in target tissues, during the perinatal period. Specificities concerning MR expression and regulation during the development of several major organs are highlighted. We provide evidence that MR expression is tightly controlled in a tissue-specific manner during development, which could have major pathophysiological implications in the neonatal period.
    Biochimie 09/2012; · 3.14 Impact Factor
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    ABSTRACT: Contexte : L’expression Sertolienne du récepteur aux androgènes (AR) est essentielle à la physiologie testiculaire et pour la spermatogenèse. SRC2 et HBO1 sont des partenaires moléculaires modulant l’activité transcriptionnelle du AR mais leur expression dans le testicule humain n’a jamais été étudiée. Objectif : Evaluer l’expression de ces 2 corégulateurs dans le testicule humain au cours du développement et en pathologie. Préciser l’androgénodépendance de leur expression ainsi que leur impact sur la signalisation androgénique sertolienne. Méthodes : Nous avons évalué par immunohistochimie et qPCR l’expression de SRC2 et de HBO1 sur des échantillons testiculaires humains au cours du développement (du fœtus à l’âge adulte). L’activité corégulatrice de SRC2 et HBO1 a été étudiée par transfection transitoire et stratégie d’interférence ARN dans les lignées sertoliennes SMAT1 et ST38c. Résultats : SRC2 est exclusivement exprimé dans les cellules de Sertoli, de façon constante de la vie fœtale (16 semaines gestation) à l’âge adulte, mais aussi chez les sujets ayant une insensibilité aux androgènes. Par contre, HBO1 n’est pas détectable dans le testicule foetal, faiblement exprimé pendant la période néonatale. Son expression augmente progressivement jusqu’à la puberté, alors qu’il est absent dans les testicules des patients avec insensibilité aux androgènes. Des doubles immunomarquages indiquent une localisation sertolienne et germinale du HBO1. In vitro, SRC2 se comporte comme un co-activateur et HBO1 comme un corépresseur du AR. Conclusion : Nous dressons la première cartographie de la distribution testiculaire de deux corégulateurs stéroïdiens au cours de l’ontogenèse testiculaire humaine et dans l’insensibilité aux androgènes.
    Annales d'Endocrinologie. 09/2012; 73(4):267.

Publication Stats

2k Citations
559.43 Total Impact Points

Institutions

  • 1995–2014
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 2013
    • Carol Davila University of Medicine and Pharmacy
      Bucureşti, Bucureşti, Romania
  • 2002–2012
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1989–2012
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Hôpital Armand-Trousseau (Hôpitaux Universitaires Est Parisien)
      Lutetia Parisorum, Île-de-France, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
  • 2005
    • Universität Heidelberg
      • Faculty of Medicine Mannheim and Clinic Mannheim
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1989–1990
    • Columbia University
      • • Department of Microbiology and Immunology
      • • College of Physicians and Surgeons
      New York City, NY, United States
  • 1986
    • Vanderbilt University
      Nashville, Michigan, United States