MAPK implications in the biological rhythms of suprachiasmatic nuclei and peripheral oscillators Neurobiologie moléculaire Pas de mots clés en anglais 612.8 Neurobiologie moléculaire Thèses et écrits académiques MAP kinase Thèses et écrits académiques Rythmes biologiques Thèses et écrits académiques Noyau suprachiasmatique Thèses et écrits académiques Chez les Mammifères, l'horloge circadienne principale est située dans les noyaux suprachiasmatiques (NSC) de l'hypothalamus, et plusieurs oscillateurs existent à la périphérie. Un système afférent conduit l'information lumineuse aux NSC pour entraîner l'horloge à 24h, alors que des systèmes efférents, tels que la synthèse de la mélatonine par la pinéale, distribuent l'information temporelle au reste de l'organisme. Deux sous-familles de  mitogen-activated protein kinases  (MAPK) sont impliquées dans les mécanismes transcriptionnels et post-traductionnels qui définissent la période de 24h de l'horloge, et qui régulent l'  arylalkylamine N-acetyltransferase  , une enzyme essentielle à la synthèse de la mélatonine.Nos résultats suggèrent qu une autre sous-famille de MAPK, les JNK, est impliquée à deux niveaux du système circadien : l'horloge moléculaire en régulant la période, et un système efférent en participant à la transcription d'enzymes nécessaires à la synthèse de la mélatonine. Most living organisms have developed endogenous biological clocks to adapt to and anticipate daily and seasonal changes in the environment. In mammals, a main circadian clock is located within the suprachiasmatic nuclei (SCN) of the hypothalamus, and multiple oscillators exist in the periphery. Autoregulatory feedback loops, where clock proteins regulate their own rhythmic expression by inhibiting the transcription of their cognate genes, constitute the circadian molecular machinery. At the level of the SCN, an afferent system conveys the light information to the SCN to entrain the clock to 24 h, while efferent systems, including the synthesis of the pineal melatonin hormone, distribute the time information to the whole organism. Transcriptional and posttranslational regulations are critical to define the 24-h period of the molecular clockwork, and to regulate the arylalkylamine N-acetyltransferase, a key enzyme for the melatonin synthesis. Recent studies have suggest that two subfamilies of mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase 1/2 and p38MAPK, are involved in these transcriptional and post-translational regulations by phosphorylating target proteins. Little is known on the role of a third subfamily of MAPK, JNK, in the circadian system. The aim of this thesis was to investigate the potential regulatory functions of JNK isoforms in both the molecular clockwork and the melatonin synthesis. Our results demonstrate that JNK isoforms display distinct activation patterns in rat-1 fibroblasts: p46 kDa and p54 kDa isoforms are both acutely phosphorylated while only p46 kDa phosphorylation level is rhythmic over the circadian cycle. We showed that the activation level of JNK is critical to properly define the period of the clock in rat-1 cells. Also, we found that JNK activation determines the pace of the oscillations in the mouse SCN and some but not all peripheral tissues. In the rat pineal gland, we established that the transient cAMP-induced activation of JNK isoforms is also necessary for the cAMPinduced transcription of several genes including Aa-Nat. Besides, both JNK and p38MAPK activation contribute to the expression of Mkp-1, a MAPK phosphatase. Altogether, our results support a role for JNK isoforms at two levels of the circadian system: the molecular clockwork by regulating the period of the clock, and the efferent system by driving the transcription of enzymes that participate to the melatonin synthesis. Electronic Thesis or Dissertation Text en France PDF https://publication-theses.unistra.fr/public/theses_doctorat/2007/CHANSARD_Mathieu_2007.pdf Université de Strasbourg Strasbourg Chansard Mathieu 1905-06-02T00:00:00 FR 116410698 http://www.theses.fr/2007STR13029 2007STR13029 2007-04-04T00:00:00 Neurosciences Université Louis Pasteur (Strasbourg) 026404540 Doctorat Docteur es non oui Simonneaux Valérie 033237778 Fukuhara Chiaki 128496444 École doctorale Sciences de la vie et de la santé (Strasbourg ; 2000-....) ED414 156502844 ddc:610