Adriano Flora

Baylor College of Medicine, Houston, Texas, United States

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Publications (23)177.72 Total impact

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    ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). To determine the long-term effects of exercise, we implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by up-regulation of epidermal growth factor and consequential down-regulation of Capicua, which is an ATXN1 interactor. Offspring of Capicua mutant mice bred to SCA1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels--either genetically or by exercise--mitigated the disease phenotypes by dampening the toxic gain of function. Thus, exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases.
    Science 11/2011; 334(6056):690-3. DOI:10.1126/science.1212673 · 31.48 Impact Factor
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    ABSTRACT: The proneural, basic helix-loop-helix transcription factor Atoh1 governs the development of numerous key neuronal subtypes, such as cerebellar granule and brainstem neurons, inner ear hair cells, and several neurons of the proprioceptive system, as well as diverse nonneuronal cell types, such as Merkel cells and intestinal secretory lineages. However, the mere handful of targets that have been identified barely begin to account for Atoh1's astonishing range of functions, which also encompasses seemingly paradoxical activities, such as promoting cell proliferation and medulloblastoma formation in the cerebellum and inducing cell cycle exit and suppressing tumorigenesis in the intestine. We used a multipronged approach to create a comprehensive, unbiased list of over 600 direct Atoh1 target genes in the postnatal cerebellum. We found that Atoh1 binds to a 10 nucleotide motif (AtEAM) to directly regulate genes involved in migration, cell adhesion, metabolism, and other previously unsuspected functions. This study expands current thinking about the transcriptional activities driving neuronal differentiation and provides a framework for further neurodevelopmental studies.
    Proceedings of the National Academy of Sciences 02/2011; 108(8):3288-93. DOI:10.1073/pnas.1100230108 · 9.81 Impact Factor
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    ABSTRACT: Granule neuron precursors (GNPs) are the most actively proliferating cells in the postnatal nervous system, and mutations in pathways that control the GNP cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic postnatal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for GNP proliferation, and demonstrate that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. Our data shed light on the function of Atoh1 in postnatal cerebellar development and identify a new mechanism that can be targeted to regulate medulloblastoma formation.
    Science 12/2009; 326(5958):1424-7. DOI:10.1126/science.1181453 · 31.48 Impact Factor
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    ABSTRACT: Mice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with congenital central hypoventilation syndrome (CCHS). We generated a Math1-GFP fusion allele to trace the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified Math1-dependent neurons and their projections near the pre-Bötzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration.
    Neuron 11/2009; 64(3):341-54. DOI:10.1016/j.neuron.2009.10.023 · 15.98 Impact Factor
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    ABSTRACT: Purpose: , Congenital neuro-respiratory disorders including Congenital Central Hypoventilation Syndrome (CCHS) cause substantial morbidity and mortality in childhood. The respiratory rhythm is modulated by multiple hindbrain nuclei, but the identities, function, and origins for many of these lineages are unknown. Mice that lack the proneural transcription factor Math1 die soon after birth from central apnea. We hypothesized that Math1 expression is required for the development of neurons critical for respiration and that Math1-lineal neurons project to nuclei known to modulate respiration. Methods: , We utilized a combination of physiological, fate mapping, and projection labeling techniques to investigate our hypotheses. Physiological analysis was derived from E18.5 murine embryos utilizing standard brain stem-spinal cord preparations and the impact of neuromodulators on the respiratory rhythm tested. We generated a new Math1-GFP fusion allele to identify neurons actively expressing Math1 in vivo and a novel progesterone inducible Math1Cre*PR allele for fate mapping. The latter allele also allowed specific Math1-projection labeling in conjunction with a reporter mouse expressing membrane-bound GFP. Results: , Math1-null mice die owing to a defect localized to the medulla and bathing with a glutamate reuptake inhibitor reestablishes the respiratory rhythm. With the Math1-GFP allele we identified a novel population of neurons that activate Math1 intraparenchymally. These neurons co-express Phox2b and Lbx1 and migrate to the position of parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN) where they co-express NK1R. In the absence of Math1, pFRG/RTN neurons fail to develop appropriately. Lastly, we found that neurons expressing Math1 at E10.5 send projections to the preBtzinger complex, the central pattern generator for the respiratory rhythm. Conclusions: , Math1 is required for proper development of the pFRG/RTN and Math1-lineal neurons send projections to the preBtzinger complex. Physiological data supports that Math1 glutamatergic neurons provide a vital excitatory drive for respiration at birth. Patients and mouse models of CCHS are known to lose the pFRG/RTN raising the possibility that it is critical for respiration. This study provides insight about the developmental lineage of these neurons, their dependency on Math1, and reveals the critical role of Math1 for development of multiple components of the respiratory network. KAA, MFR, and JR contributed equally to this work
    2009 American Academy of Pediatrics National Conference and Exhibition; 10/2009
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    ABSTRACT: Proneural factors represent <10 transcriptional regulators required for specifying all of the different neurons of the mammalian nervous system. The mechanisms by which such a small number of factors creates this diversity are still unknown. We propose that proteins interacting with proneural factors confer such specificity. To test this hypothesis we isolated proteins that interact with Math1, a proneural transcription factor essential for the establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures and identified the E-protein Tcf4. Interestingly, haploinsufficiency of TCF4 causes the Pitt-Hopkins mental retardation syndrome, underscoring the important role for this protein in neural development. To investigate the functional relevance of the Math1/Tcf4 interaction in vivo, we studied Tcf4(-/-) mice and found that they have disrupted pontine nucleus development. Surprisingly, this selective deficit occurs without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Importantly, deletion of any of the other E-protein-encoding genes does not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. Our findings provide the first in vivo evidence for an exclusive function of dimers formed between a proneural basic helix-loop-helix factor and a specific E-protein, offering insight about the mechanisms underlying transcriptional programs that regulate development of the mammalian nervous system.
    Proceedings of the National Academy of Sciences 09/2007; 104(39):15382-7. DOI:10.1073/pnas.0707456104 · 9.81 Impact Factor
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    ABSTRACT: PHOX2A is a paired-like homeodomain transcription factor that participates in specifying the autonomic nervous system. It is also involved in the transcriptional control of the noradrenergic neurotransmitter phenotype as it regulates the gene expression of tyrosine hydroxylase and dopamine-beta-hydroxylase. The results of this study show that the human orthologue of PHOX2A is also capable of regulating the transcription of the human alpha3 nicotinic acetylcholine receptor gene, which encodes the ligand-binding subunit of the ganglionic type nicotinic receptor. In particular, we demonstrated by chromatin immunoprecipitation and DNA pulldown assays that PHOX2A assembles on the SacI-NcoI region of alpha3 promoter and, by co-transfection experiments, that it exerts its transcriptional effects by acting through the 60-bp minimal promoter. PHOX2A does not seem to bind to DNA directly, and its DNA binding domain seems to be partially dispensable for the regulation of alpha3 gene transcription. However, as suggested by the findings of our co-immunoprecipitation assays, it may establish direct or indirect protein-protein interactions with Sp1, thus regulating the expression of alpha3 through a DNA-independent mechanism. As the alpha3 subunit is expressed in every terminally differentiated ganglionic cell, this is the first example of a "pan-autonomic" gene whose expression is regulated by PHOX2 proteins.
    Journal of Biological Chemistry 06/2007; 282(18):13290-302. DOI:10.1074/jbc.M608616200 · 4.60 Impact Factor
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    ABSTRACT: The specification of neuronal identity is a result of interactions between the following two distinct classes of determinants: extrinsic factors that include secreted or cell membrane-associated signals in the local environment, and intrinsic factors that generally consist of ordered cascades of transcription factors. Little is known about the molecular mechanisms underlying the interplay between these extrinsic and intrinsic factors and the transcriptional processes that establish and maintain a given neuronal phenotype. Phox2b is a vertebrate homeodomain transcription factor and a well established intrinsic factor in developing autonomic ganglia, where its expression is triggered by the bone morphogenic proteins secreted by the dorsal aorta. In this study we characterized its proximal 5'-regulatory region and found that it contained five putative DNA sites that potentially bind homeodomain proteins, including PHOX2B itself. Chromatin immunoprecipitation assays showed that PHOX2B could bind its own promoter in vivo, and electromobility gel shift assays confirmed that four of the five sites could be involved in PHOX2B binding. Functional experiments demonstrated that 65% of the transcriptional activity of the PHOX2B promoter in neuroblastoma cells depends on this auto-regulatory mechanism and that all four sites were required for full self-transactivation. Our data provide a possible molecular explanation for the maintenance of PHOX2B expression in developing ganglia, in which initially its expression is triggered by bone morphogenic proteins, but may become independent of external stimuli when it reaches a certain nuclear concentration and sustains its own transcription.
    Journal of Biological Chemistry 12/2005; 280(45):37439-48. DOI:10.1074/jbc.M508368200 · 4.60 Impact Factor
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    ABSTRACT: The dicarboximide fungicide iprodione (Ip) causes oxidative damage as a result of the production of free oxygen radicals, and induces cytochrome P4501A3 (CYP1A3) in cultured rainbow trout hepatocytes. The aim of this study was to characterise some of the molecular mechanisms by means of which Ip activates the aryl hydrocarbon receptor (AhR) and subsequently induces the CYP1A3 gene in rainbow trout (Oncorhynchus mykiss). The study was performed using primary hepatocytes and transfected HepG2 cells with a reporter construct, in which luciferase gene expression is under the transcriptional control of a multimerised xenobiotic response elements (4XREs), or a 2.3 Kb DNA fragment (corresponding to the trout CYP1A3 gene promoter). Ip exposure increased rainbow trout hepatocyte CYP1A3 mRNA over time and increased the expression of reporter gene in HepG2, thus suggesting that Ip induces the CYP1A3 gene by activating the AhR. Genistein, a tyrosine kinase inhibitor, efficiently inhibited the Ip-mediated induction of the CYP1A3 gene as demonstrated by mRNA level decrease and the impaired activation of the luciferase reporter gene constructs. Staurosporine, an inhibitor of protein kinase C, also suppressed the induction by Ip. When the AhR antagonist alpha-naphthoflavone was added to the cultures, Ip-mediated CYP1A3 induction was suppressed. These findings are consistent with a mechanism of Ip-mediated CYP1A3 gene induction that involves the activation of the AhR complex via phosphorylation-dephosphorylation reactions.
    Aquatic Toxicology 05/2005; 72(3):209-20. DOI:10.1016/j.aquatox.2004.12.009 · 3.51 Impact Factor
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    ABSTRACT: The Na+,K+-ATPase is a ubiquitous protein found in virtually all animal cells which is involved in maintaining the electrochemical gradient across the plasma membrane. It is a multimeric enzyme consisting of alpha, beta and gamma subunits that may be present as different isoforms, each of which has a tissue-specific expression profile. The expression of the Na+,K+-ATPase alpha3 subunit in humans is confined to developing and adult brain and heart, thus suggesting that its catalytic activity is strictly required in excitable tissues. In the present study, we used structural, biochemical and functional criteria to analyse the transcriptional mechanisms controlling the expression of the human gene in neurons, and identified a minimal promoter region of approx. 100 bp upstream of the major transcription start site which is capable of preferentially driving the expression of a reporter gene in human neuronal cell lines. This region contains the cognate DNA sites for the transcription factors Sp1/3/4 (transcription factors 1/3/4 purified from Sephacryl and phosphocellulose columns), NF-Y (nuclear factor-Y) and a half CRE (cAMP-response element)-like element that binds a still unknown protein. Although the expression of these factors is not tissue-specific, co-operative functional interactions among them are required to direct the activity of the promoter predominantly in neuronal cells.
    Biochemical Journal 03/2005; 386(Pt 1):63-72. DOI:10.1042/BJ20041294 · 4.78 Impact Factor
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    ABSTRACT: Mammalian NADH-cytochrome b5 reductase (b5R) is an N-myristoylated protein that is dually targeted to ER and mitochondrial outer membranes. The N-linked myristate is not required for anchorage to membranes because a stretch of hydrophobic amino acids close to the NH2 terminus guarantees a tight interaction of the protein with the phospholipid bilayer. Instead, the fatty acid is required for targeting of b5R to mitochondria because a nonmyristoylated mutant is exclusively localized to the ER. Here, we have investigated the mechanism by which N-linked myristate affects b5R targeting. We find that myristoylation interferes with interaction of the nascent chain with signal recognition particle, so that a portion of the nascent chains escapes from cotranslational integration into the ER and can be post-translationally targeted to the mitochondrial outer membrane. Thus, competition between two cotranslational events, binding of signal recognition particle and modification by N-myristoylation, determines the site of translation and the localization of b5R.
    The Journal of Cell Biology 03/2005; 168(5):735-45. DOI:10.1083/jcb.200407082 · 9.69 Impact Factor
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    ABSTRACT: : The expression of neurotransmitter receptors on the surface of immunocompetent cells is generally accepted as evidence that the nervous system can influence immune responses, even though many aspects of these interactions remain to be elucidated. In this article, we analyzed the expression of the α3 nicotinic receptor subunit in human cell lines of myeloid and lymphoid origin and show that the α3 mRNA and the receptor molecules containing this subunit are specifically expressed in T lymphocyte cell lines. We have previously characterized the structural properties of the human α3 nicotinic subunit gene promoter and defined its functional profile in neuronal cells; in this study, we analyzed the activity of the α3 promoter in T lymphocytes and found that the same minimal promoter located in the 0.16-kb BglII-AccIII fragment is responsible for the expression of the α3 mRNA in both neuronal and T lymphocyte cell lines. However, the α3 transcription initiation patterns in the two cell types were both qualitatively and quantitatively different, and the minimal promoter was differentially modulated by downstream and upstream regulatory elements. These findings suggest that distinct transcriptional mechanisms allow the same promoter to be regulated in a tissue-specific fashion, according to the different functional needs of the two cell types.
    Journal of Neurochemistry 09/2002; 71(3):1261-1270. DOI:10.1046/j.1471-4159.1998.71031261.x · 4.24 Impact Factor
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    ABSTRACT: The rainbow trout cytochrome P4501A gene subfamily consists of two members, CYP1A1 and CYP1A3, which are induced by polycyclic aromatic hydrocarbons (PAHs). In this study, we investigated the induction of cytochrome P4501A3 in the rainbow trout (Onchorhynchus mykiss) D-11 cell line after 3-methylcholanthrene (3MC) exposure by generating chimeric constructs in which a 2.3 kb fragment or portion of the 5'-flanking region of the trout cytochrome CYP1A3 gene was fused to the firefly luciferase (Luc) gene. The constructs were then transiently transfected into the trout D-11 cells and their transcriptional activity measured by luciferase assay after treatment with different 3MC concentrations. Maximal induction following exposure to 2 microM 3MC was 2.2-fold after 72 h. Deletion of the region specifying the 5' untranslated region (5'UTR) of the mRNA encoding the CYP1A3 gene increased unstimulated luciferase activity but also led to a loss of response to 3MC treatment. This finding suggests that the region specifying the 5'UTR contains a negative element that is also involved in the transcriptional response to 3MC.
    Toxicology in Vitro 09/2002; 16(4):365-74. DOI:10.1016/S0887-2333(02)00025-5 · 3.21 Impact Factor
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    ABSTRACT: Abstract : The mRNA encoding the human α5 nicotinic subunit was detected in several structures of the nervous system but appeared to be mainly expressed in cerebellum, thalamus, and the autonomic ganglia. For the first time, the α5 transcript was also detected in several non-neuronal tissues, with maximal expressions being found throughout the gastrointestinal tract, thymus, and testis. Many other extraneuronal sites expressed α5, but there were also nonexpressing organs, such as the liver, spleen, and kidney. To understand the transcriptional mechanisms controlling such a diversified expression of α5 in neuronal and nonneuronal cells, we isolated the 5′-regulatory region of the human gene and characterized its properties. Here we identify the α5 core promoter and demonstrate that the DNA regions surrounding it contain elements (with positive or negative activities) that work in a tissue-specific fashion. In particular, the segment specifying the 5′-untranslated region in neuronal cells has most of the properties of an enhancer because it activates a heterologous promoter in a position- and orientation-independent fashion. We therefore conclude that the expression of α5 relies on a highly complex promoter that uses distinct regulatory elements to comply with the different functional and developmental requirements of the various tissues and organs.
    Journal of Neurochemistry 12/2001; 75(1):18 - 27. DOI:10.1046/j.1471-4159.2000.0750018.x · 4.24 Impact Factor
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    ABSTRACT: Phox2a is a vertebrate homeodomain transcription factor that is involved in the specification of the autonomic nervous system. We have isolated the 5' regulatory region of the human Phox2a gene and studied the transcriptional mechanisms underlying its expression. We first identified the minimal gene promoter by means of molecular and functional criteria and demonstrated that its activity relies on a degenerate TATA box and a canonical Sp1 site. We then concentrated on the region immediately upstream of the promoter and found that it stimulates transcription in a neurospecific manner because its deletion caused a substantial decline in reporter gene expression only in neuronal cells. This DNA region contains a putative binding site for homeodomain transcription factors, and its mutation severely affects the transcriptional activity of the entire 5' regulatory region, thus indicating that this site is necessary for the expression of Phox2a in this cellular context. The use of the electrophoretic mobility shift assay showed that Phox2b/PMX2b is capable of specifically interacting with this site, and cotransfection experiments demonstrated that it is capable of transactivating the human Phox2a promoter. Many data obtained from knock-out mice support the hypothesis that Phox2a acts downstream of Phox2b during the development of most of the autonomic nervous system. We have provided the first molecular evidence that Phox2b can regulate the expression of Phox2a by directly binding to its 5' regulatory region.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2001; 21(18):7037-45. · 6.75 Impact Factor
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    ABSTRACT: The minimal promoter of the human alpha(3) nicotinic receptor subunit gene has been mapped to a region of 60 base pairs and found to contain two Sp1 sites, one of which is essential for promoter activity. DNase footprinting has revealed the presence of another region of interaction with nuclear factors (named F2) immediately downstream of the Sp1 sites. This region has been found to be functional since it is capable of stimulating the minimal promoter. The F2 protection is completely and specifically competed by an AP2 consensus oligonucleotide that has been proved to bind AP2alpha exclusively. However, the AP2alpha recombinant protein was unable to bind the F2 region directly, thus suggesting that AP2alpha may participate in F2 protection by protein-protein interactions with other nuclear factors. The minimal promoter has been shown to be stimulated by two additional regions, one located downstream of F2 and the other upstream of the minimal promoter itself. In neuronal cells, the combined stimulatory activities of these three regions have synergistic effects, whereas in non-neuronal cells, there is a negative interference between the upstream and downstream regions. These opposite transcriptional effects may account for at least part of the neuro-specific expression profile of the alpha(3) gene.
    Journal of Biological Chemistry 01/2001; 275(52):41495-503. DOI:10.1074/jbc.M006197200 · 4.60 Impact Factor
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    ABSTRACT: The minimal promoter of the human α3 nicotinic receptor subunit gene has been mapped to a region of 60 base pairs and found to contain two Sp1 sites, one of which is essential for promoter activity. DNase footprinting has revealed the presence of another region of interaction with nuclear factors (named F2) immediately downstream of the Sp1 sites. This region has been found to be functional since it is capable of stimulating the minimal promoter. The F2 protection is completely and specifically competed by an AP2 consensus oligonucleotide that has been proved to bind AP2α exclusively. However, the AP2α recombinant protein was unable to bind the F2 region directly, thus suggesting that AP2α may participate in F2 protection by protein-protein interactions with other nuclear factors. The minimal promoter has been shown to be stimulated by two additional regions, one located downstream of F2 and the other upstream of the minimal promoter itself. In neuronal cells, the combined stimulatory activities of these three regions have synergistic effects, whereas in non-neuronal cells, there is a negative interference between the upstream and downstream regions. These opposite transcriptional effects may account for at least part of the neuro-specific expression profile of the α3gene.
    Journal of Biological Chemistry 12/2000; 275(52):41495-41503. · 4.60 Impact Factor
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    ABSTRACT: The mRNA encoding the human alpha5 nicotinic subunit was detected in several structures of the nervous system but appeared to be mainly expressed in cerebellum, thalamus, and the autonomic ganglia. For the first time, the alpha5 transcript was also detected in several non-neuronal tissues, with maximal expressions being found throughout the gastrointestinal tract, thymus, and testis. Many other extraneuronal sites expressed alpha5, but there were also nonexpressing organs, such as the liver, spleen, and kidney. To understand the transcriptional mechanisms controlling such a diversified expression of alpha5 in neuronal and nonneuronal cells, we isolated the 5'-regulatory region of the human gene and characterized its properties. Here we identify the alpha5 core promoter and demonstrate that the DNA regions surrounding it contain elements (with positive or negative activities) that work in a tissue-specific fashion. In particular, the segment specifying the 5'-untranslated region in neuronal cells has most of the properties of an enhancer because it activates a heterologous promoter in a position- and orientation-independent fashion. We therefore conclude that the expression of alpha5 relies on a highly complex promoter that uses distinct regulatory elements to comply with the different functional and developmental requirements of the various tissues and organs.
    Journal of Neurochemistry 08/2000; 75(1):18-27. · 4.24 Impact Factor
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    ABSTRACT: The human alpha5 nicotinic receptor subunit gene appears to be expressed in several structures of the nervous system, but also in a number of non-neuronal tissues, with maximal expressions occurring in the entire gastrointestinal tract, thymus and testis. To understand whether specific transcriptional mechanisms are involved in the tissue-specific expression of the alpha5 subunit in neuronal and non-neuronal cells, we isolated the 5'-regulatory region of the human gene and characterized its functional properties. We demonstrate that specific DNA elements, with positive or negative activities depending on the cell type, are responsible for the diversified expression of the alpha5 subunit in different tissues. We therefore conclude that the expression of the alpha5 subunit relies on a highly complex promoter that uses distinct regulatory elements to comply with the different functional and developmental requirements of the various tissues and organs.
    European Journal of Pharmacology 04/2000; 393(1-3):85-95. · 2.68 Impact Factor
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    ABSTRACT: The human α5 nicotinic receptor subunit gene appears to be expressed in several structures of the nervous system, but also in a number of non-neuronal tissues, with maximal expressions occurring in the entire gastrointestinal tract, thymus and testis. To understand whether specific transcriptional mechanisms are involved in the tissue-specific expression of the α5 subunit in neuronal and non-neuronal cells, we isolated the 5′-regulatory region of the human gene and characterized its functional properties. We demonstrate that specific DNA elements, with positive or negative activities depending on the cell type, are responsible for the diversified expression of the α5 subunit in different tissues. We therefore conclude that the expression of the α5 subunit relies on a highly complex promoter that uses distinct regulatory elements to comply with the different functional and developmental requirements of the various tissues and organs.
    European Journal of Pharmacology 03/2000; 393(1):85-95. DOI:10.1016/S0014-2999(00)00040-6 · 2.68 Impact Factor

Publication Stats

654 Citations
177.72 Total Impact Points

Institutions

  • 2009–2011
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 2007
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1998–2007
    • University of Milan
      • Department of Pharmacology, Chemotherapy and Medical Toxicology
      Milano, Lombardy, Italy
  • 1999
    • Mario Negri Institute for Pharmacological Research
      • Laboratory of Molecular Biology
      Milano, Lombardy, Italy