Thèse présentée pour obtenir le grade de Docteur de l'Université Louis Pasteur

Mathieu Chansard

Description

Niveau: Supérieur, Doctorat, Bac+8
Thèse présentée pour obtenir le grade de Docteur de l'Université Louis Pasteur Strasbourg I In collaboration with the Morehouse School of Medicine Atlanta, USA Discipline: Neurosciences par Mathieu Chansard MAPK IMPLICATIONS IN THE BIOLOGICAL RHYTHMS OF SUPRACHIASMATIC NUCLEI AND PERIPHERAL OSCILLATORS ROLES DES MAPK DANS LES RYTHMES BIOLOGIQUES DES NOYAUX SUPRACHIASMATIQUES ET DES OSCILLATEURS PERIPHERIQUES Soutenue publiquement le 4 Avril 2007 Membres du jury Directeur de Thèse Mme V. Simonneaux, Directeur de Recherche, Strasbourg Co-Directeur de Thèse Mme C. Fukuhara, Assistant Professor, Atlanta Rapporteur Interne Mr F. Lasbennes, Professeur des Universités, Strasbourg Rapporteur Externe Mr F. Rouyer, Directeur de Recherche, Gif-sur-Yvette Rapporteur Externe Mr P. Voisin, Directeur de Recherche, Poitiers Examinateur Mr B. Chatton, Professeur des Universités, Illkirch

• roles des mapk dans les rythmes biologiques


• she knows


• ministère de l'education nationale


• sincerely thank


• centre national de la recherche scientifique

Sujets

• Fukuhara
• Louis Pasteur University
• Chatton
• Nashville
• Whittaker
• Woodley
• Farmer
• MacLeish

Informations

• Publié par: profil-zyak-2012
• Publié le: 01 avril 2007
• Nombre de lectures: 18
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Thèse présentée pour obtenir le grade de
Docteur de l’Université Louis Pasteur
Strasbourg I

In collaboration with
the Morehouse School of Medicine
Atlanta, USA

Discipline: Neurosciences

par Mathieu Chansard



MAPK IMPLICATIONS IN THE BIOLOGICAL RHYTHMS OF
SUPRACHIASMATIC NUCLEI AND PERIPHERAL OSCILLATORS

ROLES DES MAPK DANS LES RYTHMES BIOLOGIQUES DES
NOYAUX SUPRACHIASMATIQUES ET DES OSCILLATEURS
PERIPHERIQUES

Soutenue publiquement le 4 Avril 2007

Membres du jury

Directeur de Thèse Mme V. Simonneaux, Directeur de Recherche, Strasbourg
Co-Directeur de Thèse Mme C. Fukuhara, Assistant Professor, Atlanta
Rapporteur Interne Mr F. Lasbennes, Professeur des Universités, Strasbourg
Rapporteur Externe Mr F. Rouyer, Directeur de Recherche, Gif-sur-Yvette Mr P. Voisin, Directeur de Recherche, Poitiers
Examinateur Mr B. Chatton, Professeur des Universités, Illkirch


























This PhD was accomplished in the Neuroscience Institute of the Morehouse School of
Medicine of Atlanta in 2003-2006, and in the Département de Neurobiologie des
Rythmes of the Institut des Neurosciences Cellulaires et Intégratives of Strasbourg in
2006-2007. This work was achieved in the frame of the European Doctoral College of
the Universities of Strasbourg from 2006.

The french Ministère de l’éducation nationale, de l’enseignement supérieur et de la
recherche, the french Centre National de la Recherche Scientifique, the american
National Institute of Health, the american National Science Foundation, the Keck
Foundation and the Fondation Recherche Médicale financially supported this work.










La persévérance vient à bout de tout…


1




2 ACKNOWLEDGMENTS
ACKNOWLEDGMENTS

At first, I would like to sincerely thank Mireille Masson-Pévet, Paul Pévet and
Peter MacLeish for accepting to let me accomplish my doctoral thesis in their respective
laboratories in Strasbourg and Atlanta. Although sharing my time between the two
laboratories has not always been easy, in fine it has been for me an amazing experience !

I also would like to express my gratitude to Chiaki Fukuhara who gave me three
and half years ago the opportunity to start my PhD with her. She knows we went through
difficult times together. However, what she may not know is that I am sincerely grateful
for those moments which made me learn so much…

How can I express how much I owe to Valerie Simonneaux ? That, I may never find
out ! She encouraged me to start a PhD and later she found the right words to convince
me to finish it… and then again she managed to do it one more time ! Valerie, you are
unbelievably positive and convincing. Thank you for everything… I will not forget your
constant availability and concern. This thesis belongs to you as much as it belongs to me.

I would like to sincerely acknowledge all the members of my thesis committee,
including François Lasbennes, François Rouyer, Pierre Voisin and Bruno Chatton,
for accepting to review and judge my work.

Je remercie aussi Céline Montibeller et Catherine Naud du Collège Doctoral
Européen pour leur aide et leur gentillesse.

Working at the Neuroscience Institute of the Morehouse School of Medicine of
Atlanta has been a wonderful experience and I want to have a thought for all of you who
welcomed me so kindly. I would like to show my gratitude to Belinda Farmer and
Cathy Woodley for their constant help and infinite kindness. I also thank Joe
Whittaker, Byron Ford, and Shobu Namura for their sympathy and importantly
Gianluca Tosini for taking good care of Manami after I left ! Thank you to Ernie Steele
for his kindness, and for sharing those beers in Nashville and Washington. I will not
forget Brenda James, who always cared about me as my mother would, and Cui Mei,
Jimmy, Tabari, Talib, Kazumi and Katsuhiko with whom I shared a bench at some
point. I want to have a kind thought for DaJoie, CC, Don Ricardo, my office partners
and Patrick for our passionate talks about European “soccer” !
3ACKNOWLEDGMENTS
J’aimerais aussi remercier toutes les personnes que j’ai retrouvées lors de mon retour
à Strasbourg. Merci d’abord à tous les membres de l’équipe Simonneaux, Natalia,
Laura, Christiane, Anthony ainsi que les ex-membres Marie-Laure, Florent, Rosie,
Pedro et Ned. Merci à Etienne Challet pour ses conseils et à Jorge pour son aide dans
la relecture de ce manuscrit. Merci aussi à Daniel Bonn, Aurore Senser et Dominique
Streicher pour leur aide précieuse. Evidemment je n’oublie pas tous les doctorants et
post-doctorants du laboratoire avec qui j’ai partagé cette expérience et notamment
Corina, Domitille, Delphine, Zeina, Annika, Aurélie, Caroline, Benjamin, Laurent
T., Laurent N., Marc, Hughes, Jérôme et VJ, sans oublier mes camarades de DEA
Laurence et Céline. A tous, un grand merci.

Now, how could I not mention about my two favorites Italian guys, Jacopino and
Pier-Georgio ? The three of us shared so much for our first year in Atlanta… I do not
see how I could ever forget about those memorable moments. I really want to thank you
guys for everything, including the beers and the pasta ! We built memories for life in
Atlanta… Thanks to you too Nicole. You introduced me to the American way of life !
Ilva, I also want to warmly thank you for you infinite kindness. Thanks to you all, my
experience in Atlanta has been the best of all and your friendship really helped me to
accomplish my PhD.

Je veux aussi saluer d’autres personnes qui ont beaucoup compté pour moi pendant
cette thèse et qui me sont restées fidèles malgré ma longue absence : Véro, Erwan et
Julien pour leur amitié, et Elodie pour sa gentillesse et pour m’avoir hébergé à plusieurs
reprises. Et puis bien sûr Marie et Morgane, qui elles aussi termineront bientôt leur
thèse. Merci à toi ma Julie. Tu sais combien ton soutient m’est précieux.

Et enfin le plus important. Je souhaite remercier de tout cœur ma famille. Mes
parents d’abord, qui m’ont supporté dans tous mes choix, tous…, et qui n’ont jamais
cessé de croire en moi. C’est l’éducation que vous m’avez offert qui m’a permis d’arriver
là où je suis aujourd’hui. Mon frère Pierrot ensuite, qui a toujours été présent et qui
malgré son statut de Centralien a su reconnaître la valeur de mon propre parcours !
Finally, I want to thank you Manami, for your love, your patience, your
understanding, your support, for the strength you give me every single day and for your
continuous faith in me. This thesis is yours. 私はとても愛してる。
私の物であり、私の物常にである でも 私の中心はあなたのである。
4ABSTRACT
ABSTRACT

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 post-
translational 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
MAPKkinases (MAPK), extracellular signal-regulated kinase 1/2 and p38 , 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