CRE and TRE sequences of the rat tyrosine hydroxylase promoter are required for TH basal expression in adult mice but not in the embryo

Authors

  • Caryn Trocmé,

    1. Both authors contributed equally to this work.
    2. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS-UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France,
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  • Chamsy Sarkis,

    1. Both authors contributed equally to this work.
    2. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS-UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France,
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  • Jean-Michel Hermel,

    1. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS-UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France,
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  • René Duchateau,

    1. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS-UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France,
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  • Stephen Harrison,

    1. Center for Genome Research, AFRC, University of Edinburgh, Edinburgh, UK,
    2. Present address: National Institute of Medical Research, the Ridgeway, Mill Hill, London, UK,
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  • Michel Simonneau,

    1. Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, Gif-sur-Yvette, France,
    2. Present address: Laboratoire de Pharmacogénétique et Abords Thérapeutiques des Maladies Héréditaires, INSERM U458, Hôpital Robert Debré, Paris, France,
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  • Raya Al-Shawi,

    1. Center for Genome Research, AFRC, University of Edinburgh, Edinburgh, UK,
    2. Present address: Department of Anatomy and Developmental Biology, Royal Free Hospital School of Medicine,Rowland Hill Street, London, UK
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  • Jacques Mallet

    1. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS-UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France,
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J. Mallet, as above.

Abstract

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamine neurotransmitters, is expressed in a restricted number of areas, and subject to numerous regulations during development and in adulthood. Two transcription factor binding sites present in the proximal region of the TH gene, the TPA-responsive element (TRE) and the c-AMP responsive element (CRE), have been shown to play important roles in TH gene regulation in vitro. In order to elucidate in vivo the role of these two sites, we produced transgenic mice bearing a 5.3-kb fragment from the 5′ flanking sequence of the TH gene with mutations in either the CRE- or TRE-sites. Using the intact 5.3-kb fragment fused to two different reporter genes (HSV1-tk and lacZ), we show that this promoter fragment is able to specifically direct expression in catecholaminergic tissues both in adult mice and embryos. Interestingly, the CRE- and TRE-mutated transgenes were not expressed in adult mice, contrary to the situation in embryos where they were specifically expressed in catecholaminergic regions. These results demonstrate that the CRE and TRE play an essential role in basal TH expression in adult tissues in vivo. Moreover, they suggest that distinct transcription factors are involved in TH regulation in developing and adult tissues. In support of this, gel mobility shift experiments revealed a complex present only in embryonic tissues. Taken together, these data highlight the diversity of the mechanisms underlying the establishment and maintenance of the catecholaminergic phenotype.

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