Conclusion and future perspectives

This thesis identified the first circadian clock genes of the Madeira cockroach Rhyparobia ma-derae and showed circadian cycling of the mRNA of the core feedback loop genes period, time-less 1, and cryptochrome 2. The domain structure and daily expression profile of these genes were analyzed. The findings show that the circadian clock of the Madeira cockroach belongs to the basic type of insect clocks, which is more closely related to vertebrate clocks than to the derived clocks of D. melanogaster and A. pisum. No statistically significant circadian oscilla-tion in protein abundance of neither rmPER nor rmTIM1 were observed in western blots and immunohistochemical analysis of whole brain tissues. Instead, rmPER appears to stay nuclear at all times in R. maderae nervous tissue cells. Most likely, no rmPER-protein oscillations were observed due to low amplitude cycling and because oscillations in different circadian pacemaker cells were not phase-coupled. In addition, the anti rmPER (rabbit) antibody appeared to only recognize the nuclear form of the PER protein.

In the future, it is important that the genome of R. maderae is being sequenced. Various insect genomes are already published, but there is still no cockroach genome available. Although the genome of B. germanica has been sequenced recently, it is not available to the public at this time. Nevertheless, since the Madeira cockroach is an important model organism of circadian research, it will be necessary to obtain the genome of R. maderae in the near future. With the full genome available, it will be much easier to identify the complete set of circadian genes, design specific primers and analyze their expression. In addition to the genome, transcriptome data will also help to unravel the circadian system of cockroaches further. RNA-Seq may be employed in-stead of qPCR to obtain the circadian expression profile of various genes at once. As a next step towards analyzing the function of the circadian genes in R. maderae, gene silencing employing RNAi should be used to analyze the function of the circadian genes.

Although some functional data on hemimetabolous insects has already been published, for ex-ample by the lab of Kenji Tomioka and coworkers, there is still no single hemimetabolous insect species with at least the core feedback loop genes functionally analyzed. Since it became more and more obvious in the last decade that there are significant differences between insect species, it will be very interesting to understand how the molecular system of the circadian clock works in a more basic insect. mRNA sequence data of rmPer, rmTim1 and rmCry2 is now available, and gene silencing using RNAi in combination with running wheel assays may clarify the function of these genes.

In summary, this study provides the first data on the molecular circadian system of the cockroach R. maderae. In the future, a sequenced genome or transcriptome will help to characterize the complete set of circadian genes in R. maderae, and functional studies using RNAi will be used to clarify the function of clock genes in the Madeira cockroach. In addition, classical methods like RACE and qPCR will be used to analyze individual genes. With more sequence data avail-able, specific antibodies against additional circadian genes like CLK or CYC can be generated to further analyze the cellular expression pattern and subcellular localization.

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6 Acknowledgements

I dearly thank everyone who made this dissertation possible. First of all I would like to thank Prof. Monika Stengl for introducing me to the very interesting topic of insect chronobiology, providing the basis for my work and for her support. All members of the animal physiology labs of the Universities of Marburg and Kassel, and the Institute for Integrative Neuroanatomy, Charit´e Berlin, that I had the pleasure of getting to know, I thank for their support and many interesting conversations. The members of the examination committee I thank for taking the time to review my work and their patience. Special thanks goes to Dr. Christian Derst for his collaboration, introducing me to various molecular biology techniques, and all the leisure activities he took me to during my stay in Berlin. The department members of the University of Kassel institute of biology, especially the department of biochemistry, I wish to thank for their congenial support and help. My office roommates in Marburg and the submarine crew in Kassel I thank for their company and the nice atmosphere. My friends and my family I thank for their constant support. There were times I would have given up without you. Finally I would dearly like to thank everyone whom I forgot. In case I did forget YOU, im sorry. I really am.

Credits

Prof. Monika Stengl (1st reviewer) Prof. Mireille Sch¨afer (2nd reviewer)

Prof. Charlotte F¨orster Prof. Friedrich Herberg ...members of the examination committee.

Christian Derst Azar Massah Andreas Arendt ...contributed to this work.

Nico Funk Sarah K¨orte Christiane Werckenthin

Andreas Nolte ...proofread my writings.

Andreas Nolte Christian Flecke

El-Sayed Baz Hanzey Yasar Ildefonso Atienza L´opez

Nico Funk Sarah K¨orte Sandra S¨ohler Sandy Fastner Three coffee machines Various ornamental fish ...had to stand me as roommate.

Many thanks to all people I met during my phd thesis and that helped me by one means or another (In

alphabetical order) Andreas Arendt Thordis Arnold Ildefonso Atienza L´opez

Bianca Backasch El-Sayed Baz Jonas Benzler Daniela Bertinetti

Oliver Bertinetti Prof. Horst Bohn Florian Bolze Luzie Braulke Janis Brusius Tony Burmeister

Stefan Dippel Mandy Diskar Marie-Christine Donath

David Dreyer Christian Eichler

Basil El-Jundi Cornelia Exner Sandy Fastner Julia Fischer Christian Flecke

Nico Funk Roman Fricke Tobias Fromme

Petra Gawalek Thomas Graeff Karin Große-Mohr Ewald Grosse-Wilde

Svenja Hampl Prof. Bill Hansson Prof. Paul Hardin Stanley Heinze Michael Helwig Jennifer Hermann

Penelope Higgs Verena Hirschberg Prof. Uwe Homberg

Wolf H¨utteroth Susanne Jaguttis

Martin Jastroch Timo Kanzleiter

Martina Kern Michaela Keuper Steffen Klingenh¨ofer Prof. Martin Klingenspor

Gisela Kaschlaw Matthias Knape Holger Knieps Martin Kollmann Christopher K¨onig Sarah K¨orte Steffi Krannich J¨urgen Krieger Michael Krug Angela Kurylas

Alexia Loste Robin Lorenz Azar Massah Kathrin Muda Christine Nowack

Andreas Nolte Rebecca ¨Olkrug

Keram Pfeiffer Dominik Piston Anke Prinz Ursula Reichert Thomas Reischig

Frank Richter Katrin Riedinger

Stefanie Rulla Prof. Joachim Schachtner

Nils-Lasse Schneider Julia Schendzielorz Thomas Schendzielorz

Julia Schuckel Wolfgang W. Schwippert

Norman Seger Christin Sender Jutta Seyfarth Sandra S¨ohler Ralf Stanewsky

169

Regina Stieber Kai Stieger Sigrid St¨ohr G´abor Szerencsi Magdalene Trzcionka

Bertan T¨uremis

Martina Mappes Alexander Tups Christa Uthof Maike Vetter Matthias V¨omel

Isabel Walther

Prof. Christian Wegener HongYing Wei Christina Wollenhaupt

Hanzey Yasar Mechthild Zissel

A Appendix

5’- TGCTATCCA GGCTGTGCTT TCTCTGTACG CTTCTGGTAG AACCACTGGT ATTGTGCTGG ACTCTGGTG ATGGCGTCTC GCATACAGTA CCAATTTATG AAGGTTATGC TCTTCCCCAT GCCATCCTA CGTCTGGATC TGGCTGGCCG TGACTTGACT GACTACCTCA TGAAGATCCT GACTGAGCG TGGTTACAGC-3’

Figure A.1: Part of a Rhyparobia maderae actin coding sequence.

Gene Tissue Light Regime one-way ANOVA Cosinor zero-amplitude test

P F P

rmPer brain (-AMe) LD 12:12 0.0174 4.34 0.0561

AMe LD 12:12 0.3997 1.12 0.3018

Malpighi LD 12:12 0.0802 2.61 0.0875

brain LD 12:12 0.2001 1.74 0.0553

brain LD 6:18 0.009 5.22 0.2546

brain LD 18:6 5.7598e-05 16.15 0.0010

brain DD 6:18 0.1067 2.33 0.0724

brain DD 18:6 0.0024 7.28 0.1359

rmTim1 brain (-AMe) LD 12:12 2.961e-07 43.06 0.0054

AMe LD 12:12 0.0005 10.32 0.0010

Malpighi LD 12:12 0.1213 2.21 0.8067

brain DD 12:12 0.0017 7.91 0.0072

brain LD 6:18 3.180e-05 18.15 0.0023

brain LD 18:6 6.3010e-06 24.69 6.2e-05

brain DD 6:18 0.0024 7.24 0.8686

brain DD 18:6 8.04643e-06 23.58 1.2e-07 rmCry2 brain (-AMe) LD 12:12 2.4712e-07 44.47 0.0297

AMe LD 12:12 4.09e-05 17.27 0.0526

Malpighi LD 12:12 0.4756 2.61 0.6493

brain DD 12:12 0.0014 8.18 0.00016

brain LD 6:18 0.0157 4.47 0.0771

brain LD 18:6 0.0035 6.64 0.0619

brain DD 6:18 0.2386 1.58 0.0108

brain DD 18:6 0.0385 3.39 0.8560

Table A.1: Statistics of the qPCR experiments. All statistics were carried out as described in Materials and Methods.

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