Cell News Newsletter of the German Society for full electronic version Volume 39, 4/2013

International Meeting of the DGZ Regensburg March 18 – 21, 2014 Potsdam Summer Conferences 2014 The moment your data change scientific minds. This is the moment we work for.

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Newsletter of the German Society for Cell Biology

Preface 4 Executive Board DGZ Election 2014 - 2016 4 President: Eugen Kerkhoff (Regensburg) International Meeting 2014 in Regensburg 5 Vice President: Ralph Gräf (Potsdam) DGZ Member Meeting 2014 10

Chief Operating Officer: Oliver Gruss (Heidelberg) DGZ Awards 2014 Walther Flemming Medal 11 Secretary: Klemens Rottner (Bonn) Nikon Young Scientist Award of the DGZ 11 Werner Risau Prize 12 Advisory Board Binder Innovation Prize 12 M. Cristina Cardoso (Darmstadt) Reinhard Fässler (Martinsried) Volker Gerke (Münster) Research News Robert Grosse (Marburg) Salvatore Chiantia: A new generation of physical models for the plasma Harald Herrmann (Heidelberg) membrane to study inter-leaflet coupling and trans-membrane signaling 14 Ingrid Hoffmann (Heidelberg) Eckhard Lammert (Düsseldorf) Simone Reber: On spindle length and shape 18 Thomas Magin (Leipzig) Zeynep Ökten (München) Britta Qualmann (Jena) Future Meetings 23 Manfred Schliwa (München) Doris Wedlich (Karlsruhe) New Members/Missing Members 27

Office: Sabine Reichel-Klingmann Impressum 27 c/o Deutsches Krebsforschungs- zentrum (DKFZ) Im Neuenheimer Feld 280 69120 Heidelberg Cover image: Photography by Ralph Gräf, Potsdam. The photo shows the famous Einstein Tower, Tel.: 06221/42-34 51 which is today situated in the premises of the AIP (Leibnitz Institute for Astrophysics Potsdam). This sun observatory was build between 1919 and 1924 by the architect Erich Mendelsohn in collaboration with Fax: 06221/42-34 52 the physicist Albert Einstein and the astronomer Erwin Finlay Freundlich. The Einstein Tower is one of E-Mail: [email protected] the many UNESCO heritage sites that meeting attendees may visit aside from our 2014 special interest Internet: www.zellbiologie.de meetings in Potsdam.

Cell News 3/2013 3 PREFACE

Cell News is on-line!

Dear colleagues,

We are very happy that the second online-only issue of CellNews can now be communicated not only to all members of the DGZ, but to the entire scientific community. The DGZ board as well as our scientific advisors decided that the switch to the electronic format would be timely and necessary. I am sure you will all enjoy reading CellNews online from now on. In this issue, two young scientists introduce themselves, we advertise the program of our International Meeting and tell you more about previous DGZ meetings.

The journal and our scientific meetings will stay our main tasks in the future. In other words: it is all about communicating science! We are, therefore, very happy that we can confirm the organisation of a number of excellent meetings in 2014, which are running under der label of the DGZ. We also wish to thank all meetings organisors, who finalized the organisation of their meetings with terrific speakers from , Europe and overseas in time and despite the tight budget of the society. Please look at our an- nouncements and mark the deadlines for your favourite meeting.

We are certainly looking forward to meeting you all in Regensburg at our International Meeting in March. A thrilling and stimulating scientific program waits for you in one of the most beautiful cities of Germany!

Best wishes to all of you, Merry Christmas and an excellent New Year 2014!

Oliver Gruss

DGZ Election

The Executive Board and three members of the Advisory Board, two auditors and three members of the prize jury shall be elected for the term of office 2014 – 2016.

The candidates are:

Executive Board: Ralph Gräf (Potsdam) as President, Carien Niessen (Köln) as Vice President, Oliver Gruss (Heidelberg) as Chief Operating Officer, Klemens Rottner (Bonn) as Secretary

Advisory Board: Thomas Dresselhaus (Regensburg), Volker Gerke (Münster), Doris Wedlich (Karlsruhe)

Auditors: Marie-Christine Dabauvalle (Würzburg), Hans-Georg Mannherz (Bochum)

Prize Jury: Zoya Ignatova (Potsdam), Frank Schnorrer (Martinsried), Walter Witke (Bonn)

Members of the Executive Committee are elected among the active members by secret postal vote. The documents (information letter, ballot paper, 2 envelopes) have been sent to the DGZ members by mail. In case you have not received the documents, please contact the DGZ office by e-mail: [email protected]

For the introduction of the Executive Board candidates, please see Cell News, issue 3/2013 (p. 6-7), www.zellbiologie.de/cellnews/

Please, vote and send your ballot paper to the DGZ office by February 15, 2014

4 Cell News 3/2013 INTERNATIONAL MEETING

International Meeting of the German Society for Cell Biology

March 18 - 21, 2014, Regensburg, Germany

Organized by Eugen Kerkhoff, Thomas Dresselhaus, Stefanie Sprunck

The international meeting presents the current state of research in the rapidly developing field of Cell Biology, a fundamental discip- line for all life sciences. The format and programme of the meeting provides an international platform for presentation and discussion of the most recent and exciting achievements in cell biology. We strongly support young scientists by short talks, poster sessions and educational events such as a special session on publishing and funding.

The Meeting 2014 in Regensburg has an emphasis on combining the two evolutionary separated metazon kingdoms, the animal and plant cell biology.

The "Annual Meeting of the German Society for Matrix Biology (DGMB)" will be held in Regensburg in parallel with the "International Meeting of the German Society for Cell Biology (DGZ)". We have scheduled a combined session on "cell adhesion and signalling" for Thursday March 20th, and a party together in the evening. The meetings are partially overlapping in time (International Meeting (DGZ), Tuesday - Friday; Annual Meeting (DGMB), Thursday - Saturday) and we offer the possibility of a double registration.

In the name of the organizing committee (Eugen Kerkhoff, Thomas Dresselhaus and Stefanie Sprunck) I am happy to welcome you to join the exciting cell biology meeting in the historic city of Regensburg.

Eugen Kerkhoff

Meeting President: Exhibition & Sponsoring: Prof. Dr. Eugen Kerkhoff MCI Deutschland GmbH Department of Neurology Iohanna Vater Molecular Cell Biology Laboratory Markgrafenstr. 37 University Hospital Regensburg 10117 Berlin, Germany Franz-Josef-Strauß-Allee 11 Phone: +49 (0)30 / 204 59 37 93053 Regensburg, Germany Fax: +49 (0)30 / 20 45 9 - 50 Phone: +49 (0) 941-944-8922 E-mail: [email protected] E-mail: [email protected]

Legal Organizer (PCO): Information, Registration and Abstract Submission: MCI Deutschland GmbH Annika Bleckert www.zellbiologie2014.de Markgrafenstr. 56 10117 Berlin, Germany Phone: +49(0)30 / 204 59 27 Fax.: +49(0)30 / 204 59 50 E-mail: [email protected]

Cell News 3/2013 5 INTERNATIONAL MEETING

Guidelines for Abstract Submission Abstracts for the poster exhibition can be on any area of cell and developmental biology Maximum number of characters: 2000 characters including spaces no pictures, photos or images Deadline for submitting Abstracts is January 31, 2014

Abstract Book All abstracts will be printed in an abstract booklet that will be handed out at the registration desk at the meeting. Fee for abstract submission: EUR 35,00 Please note that abstract registration does not include conference registration. Once you have registered for the congress, the abstract fee will be refunded. Abstract Topics The program offers two poster sessions for which all together 14 different topics are provided:

S1: Rho GTPase signalling in physiology and disease S8: Microtubule nucleation S2: Neuronal signalling and optogenetics S9: Germ lines and stem cells in plants S3: Membrane transport PS1: Quantitative imaging of cell dynamics S4: Multipotential cells in animals PS2: Cell adhesion and signalling S5: Genome stability and DNA repair PS3: RNA Biology S6: Actin polymerization machines PS4: Cell biology of metastasis S7: organization GS: General Subjects

Presentation S1-S9 The short talks to be held in the Symposia (S1-S9) will be chosen on the basis of the abstracts by the symposium chairs. You can either choose to prepare a poster only or apply for a poster that should be considered for a short talk. Once the abstracts have been reviewed you will be informed whether your abstract was accepted as a poster or a short talk.

Poster Presenter (short talk) Please prepare a presentation of 15 minutes including discussion (12 + 3 min., optimally). You are also invited to prepare a poster in addition to your talk. (Poster size DIN A0, portrait format)

Poster Please prepare a poster size DIN A0, portrait format. There will be two poster-sessions. You will be informed about when to put up your poster and when to take it down.

Presentation PS1-PS4 and GS For abstracts of topics PS1-PS4 and GS you can only prepare a there are no short talks. Once the abstracts have been reviewed you will be informed whether your abstract was accepted as a poster.

Poster Please prepare a poster size DIN A0, portrait format. There will be two poster-sessions. You will be informed about when to put up your poster and when to take it down.

For any questions concerning the abstract topics please contact the Scientific Committee/Meeting Presidents: Prof. Dr. Eugen Kerkhoff | Department of Neurology | Molecular Cell Biology Laboratory | University Hospital Regensburg Franz-Josef-Strauß-Allee 11 | 93053 Regensburg, Germany | Phone: +49 (0)941 944 8922 | [email protected] For any questions concerning the abstract procedure please contact MCI Deutschland GmbH | Annika Bleckert | Markgrafenstr. 56 | 10117 Berlin, Germany Phone: +49 (0)30 204 59 0 | Fax.: +49 (0)30 204 59 50 | E-Mail: [email protected]

6 Cell News 3/2013 INTERNATIONAL MEETING

Tuesday, March 18, 2014 Registration 14:00 – 14:30 Robert F. Murphy (Pittsburgh, USA): 09:00 – 12:00 Funding and Publishing Image-derived spatiotemporal models of subcellular Chairs: Eugen Kerkhoff (Regensburg, Germany) and organization, differentiation and perturbation Klemens Rottner (Bonn, Germany) 14:30 – 15:00 Ivo Sbalzarini (Dresden, Germany): – Astrid Klingen (DFG, Bonn, Germany) Uniting image reconstruction and segmentation – Ulrich Genschel (ERC, Brussels, Belgium) for fluorescence microscopy 10:00 – 10:30 Coffee Break 15:00 – 15:30 Coffee Break – Bernd Pulverer (EMBO Journal, Heidelberg, Germany) 15:30 – 17:30 DGZ Awards Ceremony – Anne Knowlton (Current Biology, London, UK) – Walter Flemming Medal – Ian Mulvany (Elife, Cambridge, UK) – Binder Innovation Prize 12:00 – 13:00 Break – Werner Risau Prize – Nikon Young Scientist Award of the DGZ 13:00 – 15:00 Plenary Session PS1: – ASCB Inaugural Kaluza Prize Quantitative imaging of cell dynamics sponsored by Beckman Coulter Chair: Ivo Sbalzarini (Dresden, Germany) 17:30 – 18:00 Coffee Break 13:00 – 13:30 Erik Meijering (Rotterdam, The Netherlands): Challenges in particle and cell tracking 18:00 – 19:00 Carl Zeiss Lecture Ernst H.K. Stelzer (Frankfurt, Germany) 13:30 – 14:00 Badrinath Roysam (Houston, USA): Computational sensing of cell & tissue changes 19:00 Welcome Reception from microscopy data

Wednesday, March 19, 2014 09:00 – 12:00 Symposia 1 – 3 10:15 – 10:45 Coffee Break 09:00 – 12:00 Symposium S1: 10:45 – 11:00 Short talk speaker selected from the abstracts Rho GTPase signalling in physiology and disease 11:00 – 11:30 Alexxai Kravitz (Bethesda, USA): Chair: Cord Brakebusch (Copenhagen, Denmark) Motion and emotion in the basal ganglia 09:00 – 09:30 Zhenbiao Yang (Riverside, USA): 11:30 – 12:00 Edward Ziff (New York, USA): Rho GTPase signaling in plant cell polarity Synaptic regulation by pain and reward 09:30 – 10:00 Bernhard Nieswandt (Würzburg, Germany): 09:00 – 12:00 Symposium S3: Membrane transport Rho GTPases in platelets production and function Chair: Gerd Jürgens (Tübingen, Germany) 10:00 – 10:15 Short talk speaker selected from the abstracts 09:00 – 09:30 Scott D. Emr (Ithaca, USA): 10:15 – 10:45 Coffee Break A Ubiquitin-dependent protein quality control system at the plasma membrane 10:45 – 11:15 Scott Russo (New York, USA): Epigenetic regulation of Rac1 induces synaptic 09:30 – 10:00 Victor Žárský (, Czech Republic): remodeling in stress disorders Exocyst complex and logistics of endomembrane traffic in plants 11:15 – 11:45 Cord Brakebusch (Copenhagen, Denmark): N-WASP function in skin inflammation 10:00 – 10:15 Short talk speaker selected from the abstracts 11:45 – 12:00 Short talk speaker selected from the abstracts 10:15 – 10:45 Coffee Break 09:00 – 12:00 Symposium S2: Neuronal signalling and optogenetics 10:45 – 11:15 Gerd Jürgens (Tübingen, Germany): Chair: Edward Ziff (New York, USA) Plant cytokinesis - a tale of membrane traffic and fusion 11:15 – 11:45 Naoko Mizuno (Martinsried, Germany): 09:00 – 09:30 Ehud Isacoff (Berkeley, USA): Molecular mechanism of curvature formation Optical control of neurotransmitter gated by BAR proteins glutamate receptors 11:45 – 12:00 Short talk speaker selected from the abstracts 09:30 – 10:00 Jonathan Britt (Montreal, Canada): Neural mechanisms underlying behavioral 12:00 Lunch reinforcement in the basal ganglia 12:00 – 13:00 Lunch Symposium 1 10:00 – 10:15 Short talk speaker selected from the abstracts 13:00 – 14:00 DGZ Member Meeting

Cell News 3/2013 7 INTERNATIONAL MEETING

14:00 – 17:00 Symposia 4 – 6 15:45 – 16:15 Jerome Dejardin (Montpellier, France): 14:00 – 17:00 Symposium S4: Multipotential cells in animals DNA methylation controls the nature of Chair: Elly Tanaka (Dresden, Germany) heterochromatin in stem cells 14:00 – 14:30 Ian Chambers (Edinburgh, UK): 16:15 – 16:45 Charles Thomas (La Jolla, USA): Transcription factor control of transitions LINE-1 retrotransposition in the brain and in pluripotent cell states neurological disorders 14:30 – 14:45 Short talk speaker selected from the abstracts 16:45 – 17:00 Short talk speaker selected from the abstracts 14:45 – 15:15 Kaisuke Kaji (Edinburgh, UK): The roads to iPS cells 14:00 – 17:00 Symposium S6: Actin polymerization machines 15:15 – 15:45 Coffee Break Chair: Jan Faix (Hannover, Germany) 14:00 – 14:30 Jan Faix (Hannover, Germany): 15:45 – 16:15 Elly Tanaka (Dresden, Germany): Molecular analyses of actin polymerization maschines Molecular foundations of vertebrate regeneration 14:30 – 15:00 Laurent Blanchoin (Grenoble, France): 16:15 – 16:30 Short talk speaker selected from the abstracts Directed actin self assembly and motility 16:30 – 17:00 Wieland Huttner (Dresden, Germany): 15:00 – 15:15 Short talk speaker selected from the abstracts The cell biology of stem and progenitor cells in the developing neocortex 15:15 – 15:45 Coffee Break 14:00 – 17:00 Symposium S5: Genome stability and DNA repair 15:45 – 16:15 Roberto Dominguez (Philadelphia, USA): Chair: M. Cristina Cardoso (Darmstadt, Germany) Leiomodin and Tropomodulin and their roles in Tropomyosin-dependent actin filament nucleation 14:00 – 14:30 John Diffley (London, UK): and pointed end capping Mechanism and regulation of DNA replication origin firing in yeast 16:15 – 16:45 Rong Li (Kansas City, USA): The function of Arp2/3-based actin nucleation 14:30 – 15:00 Gary H. Karpen (Berkeley, USA) in cell motility and development 15:00 – 15:15 Alexander Rapp (Darmstadt, Germany): 16:45 – 17:00 Short talk speaker selected from the abstracts Combined genome-wide and 3D super-resolution nanoscopy analysis of the DNA damage response 17:00 – 19:00 Poster Session 1 15:15 – 15:45 Coffee Break

Thursday, March 20, 2014 09:00 – 12:00 Symposia 7 – 9 09:00 – 09:30 Elmar Schiebel (Heidelberg, Germany): 09:00 – 12:00 Symposium S7: Chromatin organization Microtubule nucleation by gamma-tubulin complexes: Chair: Gernot Längst (Regensburg, Germany) the influence of GTP binding, gamma-tubulin receptors 09:00 – 09:15 Short talk speaker selected from the abstracts and drugs 09:15 – 09:45 Peter R. Cook (Oxford, UK): 09:30 – 10:00 Jens Lüders (Barcelona, Spain): Transcription factories: genome organization Microtubule nucleation during and gene regulation 10:00 – 10:15 Short talk speaker selected from the abstracts 09:45 – 10:15 Antoine H.F.M. Peters (Basel, Switzerland): 10:15 – 10:45 Coffee Break Epigenetic control of mammalian germ line and early embryonic development 10:45 – 11:15 Anne-Catherine Schmit (Strasbourg, France): The Arabidopsis GIP proteins at the interface 10:15 – 10:45 Coffee Break between the nucleoplasm and the cytoplasm 10:45 – 11:00 Short talk speaker selected from the abstracts 11:15 – 11:45 Irina Kaverina (Nashville, USA): 11:00 – 11:30 Gernot Längst (Regensburg, Germany): Regulation and functions of Golgi-derived microtubules Dynamic changes of chromatin structure 11:45 – 12:00 Short talk speaker selected from the abstracts by RNP complexes and remodeling enzymes 09:00 – 12:00 Symposium S9: Germ lines and stem cells in plants 11:30 – 12:00 Toshio Tsukiyama (Seattle, USA): Chair: Thomas Dresselhaus (Regensburg, Germany) Regulation, functions and evolution of non-coding RNA 09:00 – 09:30 Thomas Dresselhaus (Regensburg, Germany): 09:00 – 12:00 Symposium S8: Microtubule nucleation Peptide and calcium signaling during double fertilization Chair: Jens Lüders (Barcelona, Spain)

8 Cell News 3/2013 INTERNATIONAL MEETING

09:30 – 10:00 David Twell (Leicester, UK): 15:30 – 16:00 Charles Streuli (Manchester, UK): Patterning and control in plant male germline Deconstructing adhesion complexes: development how integrins control different phenotypes 10:00 – 10:15 Short talk speaker selected from the abstracts 16:00 – 16:30 Nick Brown (Cambridge, UK): Dialogue between cell adhesion and the 10:15 – 10:45 Coffee Break cytoskeleton in morphogenesis 10:45 – 11:15 Thomas Laux (Freiburg, Germany): 16:30 – 17:00 Coffee Break Stem cell regulation in plants 17:00 – 17:30 Gregory Giannone (Bordeaux, France): 11:15 – 11:45 Renze Heidstra (Wageningen, The Netherlands): Deciphering the regulation of integrin activation Patterning and maintenance of the Arabidopsis at the nanoscale root stem cell niche 17:30 – 18:00 Daniel Müller (Zurich, Switzerland): 11:45 – 12:00 Short talk speaker selected from the abstracts Deciphering molecular mechanisms guiding cell 12:00 Lunch shape in mitotisis 12:00 – 13:00 Lunch Symposium 2 18:00 – 18:15 Break 13:00 – 15:00 Poster Session 2 18:15 – 19:15 Frontiers in Science Lecture Eugene Myers (Dresden, Germany) 15:00 – 18:00 Plenary Session PS2: Cell adhesion and signalling Chairs: Susanne Grässel (Regensburg, Germany) and 19:15 Party Reinhard Fässler (Martinsried, Germany) 15:00 – 15:30 Sara Wickström (Cologne, Germany): Cytoskeletal regulation of cell fate decisions

Friday, March 21, 2014 09:00 – 12:00 Plenary Session PS3: RNA Biology 13:15 – 16:15 Plenary Session PS4: Cell biology of metastasis Chair: Gunter Meister (Regensburg, Germany) Chair: Christoph Klein (Regensburg, Germany) 09:00 – 09:30 René Ketting (Mainz, Germany): 13:15 – 13:45 Christoph Klein (Regensburg, Germany): Transgenerational effects of small RNAs Molecular profiling of metastatic precursor cells 09:30 – 10:00 Olivier Voinnet (Zurich, Switzerland): 13:45 – 14:15 Peter Friedl (Nijmegen, The Netherlands): RNA silencing in planst and animals Plasticity of cancer cell invasion 10:00 – 10:30 Gunter Meister (Regensburg, Germany): 14:15 – 14:45 Ben Z. Stanger (Philadelphia, USA): Regulation of microRNA biogenesis and function Functionally dissecting the microenvironment 10:30 – 11:00 Coffee Break in pancreatic cancer 11:00 – 11:30 Andrea Ventura (New York, USA): 14:45 – 15:15 Coffee Break Functional deconstruction of an oncogenic 15:15 – 15:45 Cyrus Ghajar (Seattle, USA): miRNA cluster Regulation of breast tumor dormancy by 11:30 – 12:00 Maite Huarte (Pamplona, Spain): the perivascular niche Epigenetic control of cancer pathways by lncRNAs 15:45 – 16:15 David Lyden (New York, USA): 12:00 Lunch Tumor-derived exosomes promote organ-specific metastasis 13:00 – 13:15 Poster Award Ceremony 16:15 -16:30 Concluding Remarks

www.zellbiologie2014.de

Cell News 3/2013 9 DGZ MEMBER MEETING

DGZ Member Meeting 2014

We are inviting all members to attend our next member meeting that will take place on Wednesday, March 19, 2014, 13:00 at the International Meeting of the DGZ in Regensburg.

Agenda: 1. Confirmation of the minutes of the last year’s DGZ member meeting 2013 2. The president’s annual report 3. Financial report 4. The auditors’ report 5. Approval of the executive board 6. DGZ election 2014 – 2016 7. Change of the DGZ bylaws 8. „Other“

The DGZ executive board

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WALTHER FLEMMING MEDAL 2014

The German Society for Cell Biology offers a research award named after Walther Flemming, one of the pioneers of cell biological research. In 1875 he provided us with a detailed description of processes during cell division, which he named mitosis. The Walther Flemming Medal is awarded annually for outstanding scientific merits from all fields of cell biological research. Eligible are researchers up to an age of 38 years. The award consists of the medal itself and a prize money of EUR 2000 and is sponsored by the European Journal of Cell Biology. Applications have to consist of a cover letter, a CV and a list of publications. The subject of the application should relate to one distinct field of research. In addition, a short summary of the work and a compelling description of the importance of the work for cell biology should be presented. Both individual applications and nominations are accepted. Applications will be reviewed by an independent commission of the DGZ. The award ceremony takes place at the next DGZ meeting, which will be held on March 18-21, 2014 in Regensburg. Please send your application by e-mail (and in parallel one hard copy by mail) to the DGZ office: Deutsche Gesellschaft für Zellbiologie e.V. (DGZ) Sekretariat, z.H. Frau Reichel-Klingmann c/o Deutsches Krebsforschungszentrum | Im Neuenheimer Feld 280 | D-69120 Heidelberg E-mail: [email protected]

Deadline for applications: January 15, 2014

NIKON YOUNG SCIENTIST AWARD OF THE DGZ 2014

The German Society for Cell Biology (DGZ) and Nikon GmbH offer a “Nikon Young Scientist Award of the German Society for Cell Biology“ for PhD students or young postdocs (within 3 years after graduating). The award comprises a prize money of EUR 1500, sponsored by Nikon GmbH. Candidates are invited to apply for the prize by themselves or may be suggested by others. DGZ membership is required. Applications have to consist of a cover letter, a CV and PDF-files of publications that document the work of the applicant. Applications will be reviewed by an independent commission of the DGZ. The award ceremony takes place at the next DGZ meeting, which will be held on March 18-21, 2014 in Regensburg. Please send your application by e-mail (and in parallel one hard copy by mail) to the DGZ office:

Deutsche Gesellschaft für Zellbiologie e.V. (DGZ) Sekretariat, z.H. Frau Reichel-Klingmann c/o Deutsches Krebsforschungszentrum | Im Neuenheimer Feld 280 | D-69120 Heidelberg E-mail: [email protected]

Deadline for applications: January 15, 2014

Cell News 3/2013 11 DGZ AWARDS 2014

WERNER RISAU PRIZE 2014 FOR OUTSTANDING STUDIES IN ENDOTHELIAL CELL BIOLOGY

The German Society for Cell Biology (DGZ) and the Werner-Risau-Prize committee will award a prize for "outstanding studies in endothelial cell biology" to candidates within the first five years after obtaining their PhD or MD (except in case of maternal leave). The prize will be awarded for an article already published or in press, and consists of a personal diploma and a financial contribution of EUR 4000. For further details please visit: www.werner-risau-prize.org

Applicants are requested to send a letter of motivation together with their CV and one copy of the article by email (preferably in pdf format) to the Werner Risau Prize Committee c/o Prof. Dr. Rupert Hallmann Institute for Physiological Chemistry and Pathobiochemistry Westfaelische Wilhelms-Universitaet Muenster | Waldeyerstr. 15 | D-48149 Muenster, Germany E-mail: [email protected]

Deadline for applications: January 15, 2014

The prize will be awarded during the International Meeting of the German Society for Cell Biology (March 18 -21, 2014) in Regensburg, Germany.

BINDER INNOVATION PRIZE 2014

The BINDER Innovation Prize is founded by BINDER GmbH in Tuttlingen and awarded by the German Society for Cell Biology (DGZ). It is endowed with EUR 4000 and was awarded the first time in 1998. The award is given for outstanding cell biological research with a focus on cell culture or the use of cell cultures. Candidates may apply for the prize themselves. DGZ membership is desired but not required. Applications have to consist of a cover letter, CV and a research profile. Applications will be reviewed by an independent commission of the DGZ. The award ceremony takes place at the next DGZ meeting, which will be held on March 18-21, 2014 in Regensburg. Please send your application by e-mail (and in parallel one hard copy by mail) to the DGZ office: Deutsche Gesellschaft für Zellbiologie e.V. (DGZ) Sekretariat, z.H. Frau Reichel-Klingmann c/o Deutsches Krebsforschungszentrum | Im Neuenheimer Feld 280 | D-69120 Heidelberg E-mail: [email protected]

Deadline for applications: January 15, 2014

12 Cell News 3/2013 Certain configurations of this product are not available for sale in the U.S.A.

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A new generation of physical models for the plasma membrane to study inter-leaflet coupling and trans-membrane signaling

Salvatore Chiantia

Abstract asymmetry. In other words, while the cytoplasmic leaflet of Cellular membranes are complex biological entities which per- the PM contains mostly unsaturated aminophospholipids (e.g. form a wide range of functions. The lateral organization of lipids phosphatidylserine (PS), phosphatidylethanolamine (PE)) and and receptors of the plasma membrane (PM) into ordered do- inositol-based phospholipids, the outer leaflet is rich in satura- mains (e.g. raft domains) is involved in several biological proces- ted sphingolipids, such as sphingomyelin (SM) and gangliosides ses such as cell-cell communication or viral infections. (Bretscher, 1972; Devaux, 1991). Although this specific lipid dis- In order to understand the structure and function of complex tribution was clearly demonstrated for the PM of erythrocytes biological membranes, artificial bilayers have been used in the at first (Rothman and Lenard, 1977), membrane asymmetry was past as simple and well-defined physical models. Nevertheless, eventually also observed in several other biological systems, until recently, such model bilayers have not taken into account including viruses, fibroblast phagosomes, platelets and other the important compositional asymmetry between inner and ou- membranes of eukaryotic cells (Rothman and Lenard, 1977; Fa- ter leaflets of PM. deel and Xue, 2009). The trans-membrane distribution of cho- The introduction of the novel asymmetric PM models descri- lesterol, which can quickly flip between inner and outer leaflet, bed here represents an important step forward in the field of remains controversial. membrane biophysics and will provide the chance to understand Since a lipid bilayer with an asymmetric composition is not in in general how the structure and function of lipid-protein do- an equilibrium state, a complex ATP-dependent protein machi- mains are affected by leaflet compositional asymmetry and by nery is required to catalyze and direct the otherwise slow and the coupling between leaflets. random trans-bilayer dynamics. Why would a cell invest such a considerable amount of energy to generate and maintain a Trans-membrane compositional asymmetry of specific asymmetric lipid distribution in the PM? Evidence accu- biological membranes mulated that PM asymmetry is in fact involved in a large num- Cellular membranes, and in particular the plasma membra- ber of physiological and pathological events. The enrichment of ne (PM), are characterized by a transversal lipid composition PS in the cytoplasmic leaflet is connected to cellular processes

Figure 1. Membrane compositional asymmetry influences membrane curvature: (A) Confocal fluorescence microscopy images of GUVs (symmetric composition) containing phosphatidylcholine, SM and cholesterol. Such lipid composi- tion displays phase separation into ordered (raft-like) and disordered domains, shown in green and red respectively. Scale bar is 20 µm. B) SM in the outer leaflet is enzymatically converted into ceramide (the enzyme is confined to the external milieu of the vesicles). Since ceramide has a negative intrinsic mo- nolayer curvature, its accumulation in the outer leaflet of GUV modifies bilayer curvature, causing inward budding of the membrane. Scale bar is 2 µm. C) After some minutes, the budding process is complete and the interior of GUVs is filled with small vesicles. Interestingly, the fact that the budded vesicles are strongly labeled with the green fluorescent probe confirms that they originated selectively from the ordered raft-like domains of the membrane. Scale bar is 10 µm. This simple mechanism seems to be involved in lipid sorting in endosomes (see text). Adapted from (Trajkovic et al., 2008).

14 Cell News 3/2013 RESEARCH NEWS

such as apoptosis and cell differentiation (Balasubramanian and 2011). Of interest, according to the extensive experimental data Schroit, 2003). Perturbation of lipid asymmetry in several ty- provided by biophysical model system studies, lipid mixtures mi- pes of cells was observed in the context of some pathological micking the outer leaflet of the PM can give rise to raft-like or- conditions, e.g. tumors, diabetes and bleeding disorders (Fadeel dered domains. On the other hand, lipid mixtures corresponding and Xue, 2009). Furthermore, the uneven distribution of lipid to typical inner leaflet compositions form membranes that are species between the leaflets of a membrane bilayer determines homogeneous (Wang and Silvius, 2001). Therefore, in the frame- its physical properties, such as permeability, negative surface work of the raft model, the physical state and properties of the charge (of the inner leaflet) and local curvature/shape (Rothman inner leaflet of the PM are still not well understood. and Lenard, 1977; Holzer et al., 2010). Membrane curvature in particular is strongly connected to the intrinsic monolayer cur- Interaction between membrane leaflets: vature of specific lipids: a lipid with e.g. a small polar head has role in trans-membrane coupling a negative intrinsic curvature and will tend to bend a monolay- Signal transduction across the PM requires the passage of infor- er inwards. In this context, we have shown that enrichment of mation from outside a cell to its inside and is usually triggered ceramide (i.e. a sphingolipid with negative intrinsic curvature) by clustering or activation of receptors in the outer leaflet, i.e. localized in one leaflet of giant unilamellar vesicles (GUVs) led on the extracellular side (Simons and Gerl, 2010). It is known to spontaneous budding of small vesicles towards the lumen of that concerted reorganization of e.g. GPI-anchored receptors in the GUV, as shown in Fig.1. This observation provided insights the outer leaflet of the PM and lipid-anchored signaling mole- into the molecular basis for a lipid-mediated ESCRT-indepen- cules in the inner leaflet, such as Src-family kinases, is involved dent mechanism of membrane and cargo sorting in endosomes in signal transduction (Stefanova et al., 1991). While clustering (Trajkovic et al., 2008). and lateral organization of outer leaflet components might be Transversal lipid asymmetry is also associated with the lateral mediated by the presence of ordered domains, it is unclear how organization of lipids and proteins of the PM into domains. lipid-anchored signaling molecules are recruited to the same Although still object of debate, the existence of nanoscale, position and clustered (since the inner leaflet does not support cholesterol-rich dynamic protein-lipid domains (sometimes formation of lipid protein domains, see Fig.2). This raises the called “rafts”) is strongly supported by recent technical advan- general question of how leaflets´ physical properties are coup- ces (Simons and Gerl, 2010). Such ordered assemblies of lipids led, and what are the functional consequences of inter-leaflet and proteins have been extensively studied in the last 20 years coupling. in connection with a variety of biological processes including In a similar context, the physical state of the cytosolic side of immune response, cell-cell communication, viral infections and PM domains might affect the lateral organization of trans- membrane trafficking (Simons and Ikonen, 1997; Veit and Thaa, membrane receptors. This is of great importance in the field of

Figure 2. Membrane reorganization during signaling initiation: 1) Clustering of trans-membrane proteins or outer leaflet-associated receptors causes formation of stable ordered domains (pink). 2) Inner leaflet-associ- ated kinases are recruited to the same location in order to continue the signaling cascade. The physical state and properties of the cytoplasmic leaflet of the PM (especially in correspondence with ordered raft-like domains in the outer leaflet) is still not understood.

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Figure 3. Partitioning of a trans-membrane protein between ordered and disordered domains: In symmetric model membranes, the ordered domains are rich in ordering lipids (e.g. SM and cholesterol, pink) in both leaflets. In the PM (modeled by asymmetric bilayers), the ordered domains are rich in ordering lipids on the extracellular side, but rich in disordering lipids (e.g. unsaturated phospholipids, blue) on the cytosolic side. Since protein partitioning is strongly affected by lipid order, membrane asymmetry might play an important role in this process.

membrane biophysics in general, because the origin of mem- mechanisms involved in inter-leaflet coupling have been sug- brane protein affinity for lipid rafts remains to date unknown gested to include cholesterol trans-bilayer dynamics, electro- (see Fig.3). static interactions and lipid acyl chain interdigitation. By using Despite the strong biological relevance of these questions, a fluorescence correlation spectroscopy (FCS), we monitored lipid systematic biophysical investigation could not be performed diffusion (i.e. membrane order) separately in each leaflet as a until now, due to the absence of physical models of PM asym- function of lipid composition. We were able to show that the metry. Nearly all membrane biophysical studies in the last de- presence of SM from bovine milk (i.e. an interdigitating lipid cades have been in fact performed on symmetric lipid bilayers with acyl chain significantly longer than the sphingoid back- and, therefore, might have provided only partial insights into bone) in the outer leaflet induced an ordering effect also in the PM structure and organization. inner leaflet (see Fig.3). This finding is particularly interesting in light of the fact that the presence of interdigitating sphin- Asymmetric lipid bilayers as advanced models golipids is necessary for a correct trans-membrane signaling in of the plasma membrane neutrophils (Iwabuchi et al., 2010). By analyzing different lipid In order to fill this significant knowledge gap, we and other compositions, we could conclude that inter-leaflet coupling de- groups have recently developed new and advanced model mem- pends on both length and saturation of lipid acyl chains (Chian- brane systems that can effectively mirror PM compositional tia and London, 2012). The molecular mechanism likely involves asymmetry. Asymmetric supported lipid bilayers have been pre- van der Waals interactions between the terminal portions of the pared using vesicle fusion, sequential depositing of monolayers acyl chains of facing lipid molecules occurring at and near the or a combination of the two approaches (Garg et al., 2007; Wan bilayer midplane (Fig.3B). et al., 2008). However, such systems might be limited in terms In conclusion, the above-mentioned advanced biophysical mo- of what kind of experiments can be carried out and are sub- dels of the PM might allow a better understanding of lipid- jected to the influence of the solid support. Leaflet-by-leaflet mediated inter-leaflet coupling and signal transduction through assembly of free-standing membranes has also been reported the PM in the future, also in connection with the role of ste- (Pautot et al., 2003). Nevertheless, it is a concern that these rols and membrane proteins. Furthermore, asymmetric bilayers bilayers may incorporate the organic solvents used (e.g. mineral could clarify the role of PM compositional asymmetry in de- oil). Therefore, we have developed a method based on methyl- termining its three-dimensional structure (i.e. membrane cur- -cyclodextrin mediated outer leaflet exchange, in order to pro- vature) and protein partition into lipid domains. The relationship duce asymmetric vesicles with sizes ranging from 100 nm (small between PM asymmetry and receptor lateral organization has in or large unilamellar vesicles (SUVs or LUVs)) to 100 µm (GUVs) fact only very recently started to be addressed systematically in (Cheng et al., 2009; Cheng and London, 2011; Chiantia et al., controlled systems (Hussain et al., 2013). 2011). This approach is fast, has a high yield, makes use of con- ventional vesicle preparation techniques and can be used with a References wide variety of lipids (Son and London, 2013). Furthermore, this Balasubramanian K, Schroit AJ (2003). Aminophospholipid asymmetry: A matter of life and death. Annu Rev Physiol 65, 701-734. methodology is fully compatible with the most common protein Bretscher MS (1972). Asymmetrical lipid bilayer structure for biological membranes. Nat New reconstitution protocols. Biol 236, 11-12. In order to study inter-leaflet coupling, we have produced Cheng HT, London E (2011). Preparation and properties of asymmetric large unilamellar ve- sicles: interleaflet coupling in asymmetric vesicles is dependent on temperature but not cur- asymmetric GUVs with a biologically relevant composition, i.e. vature. Biophys J 100, 2671-2678. with an outer leaflet rich in SM and an inner leaflet rich in phos- Cheng HT, Megha, London E (2009). Preparation and properties of asymmetric vesicles that phatidylcholine (Chiantia and London, 2012). Specific molecular mimic cell membranes: effect upon lipid raft formation and transmembrane helix orientation. J Biol Chem 284, 6079-6092.

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Figure 4. Coupling of physical properties (lipid diffusion) between inner and outer leaflet depends on lipid composition: A) Asymmetric GUVs were prepared with different lipid compositions. Here, as an example, two compositions are shown: dioleoylphosphatidylcholine in the inner leaflet and, in the outer leaflet, either SM from porcine brain (DOPCi/bSMo) or SM from bovine milk (DOPCi/mSMo). The main difference between mSM and bSM is the length of their acyl chain: the long acyl chain of mSM can in fact penetrate (interdigitate) into the opposite (i.e. inner) leaflet. The graph in this panel shows lipid diffusion (approximately related to local membrane order) in the inner leaflet as a function of the same parameter in the outer leaflet. Each black circle refers to a single DOPCi/bSMo GUV. Grey triangles refer to single DOPCi/mSMo GUVs. The square in position (100,100) indicates the values measured in a symmetric DOPC GUV, used as a reference. The measured points span a large window in the x-direction, since the observed vesicles contain varying amounts of SM in the outer leaflet (i.e. SM in the outer leaflet induces ordering of the outer leaflet in a concentration-dependent fashion). It appears that, in correspondence with a given state of the outer leaflet, the inner leaflet of asymmetric GUVs containing interdigitating mSM in the outer leaflet is more ordered compared to GUVs containing non-interdigitating bSM in the outer leaflet. In other words, the inner leaflet of DOPCi/mSMo GUVs mirrors more closely (i.e. is more coupled) to the outer leaflet, compared to the situation observed in DOPCi/bSMo GUVs. The dash-dot line has unitary slope (i.e. maximum coupling); the dashed line has null slope (i.e. zero coupling). B) Schematic model of asymmetric bilayer with inner leaflet composed of DOPC (blue) and outer leaflet composed of mSM (black). The green rectangle indicates the region near the bilayer mid-plane, where acyl chains from opposing leaflets might interact thus inducing inter-leaflet coupling. The red lines represent the long interdigitating acyl chains of mSM. Adapted from (Chiantia and London, 2012).

Chiantia S, London E (2012). Acyl chain length and saturation modulate interleaflet coupling Salvo Chiantia studied Physics in in asymmetric bilayers: effects on dynamics and structural order. Biophys J 103, 2311-2319. Chiantia S, Schwille P, Klymchenko AS, London E (2011). Asymmetric GUVs prepared by Mbe- the University of Palermo where he taCD-mediated lipid exchange: an FCS study. Biophys J 100, L1-3. graduated in 2003. In 2008, he re- Devaux PF (1991). Static and dynamic lipid asymmetry in cell membranes. Biochemistry 30, ceived his PhD in Physics under the 1163-1173. Fadeel B, Xue D (2009). The ins and outs of phospholipid asymmetry in the plasma membrane: supervision of Prof. Schwille in the roles in health and disease. Crit Rev Biochem Mol Biol 44, 264-277. TU-Dresden, working on a combi- Garg S, Ruhe J, Ludtke K, Jordan R, Naumann CA (2007). Domain registration in raft-mimi- nation of AFM and single-molecu- cking lipid mixtures studied using polymer-tethered lipid bilayers. Biophys J 92, 1263-1270. Holzer M, Momm J, Schubert R (2010). Lipid transfer mediated by a recombinant pro-sterol le fluorescence for the study of li- carrier protein 2 for the accurate preparation of asymmetrical membrane vesicles requires a pid membranes. Between 2009 narrow vesicle size distribution: a free-flow electrophoresis study. Langmuir 26, 4142-4151. and 2012, he worked as a research Hussain NF, Siegel AP, Ge Y, Jordan R, Naumann CA (2013). Bilayer asymmetry influences integrin sequestering in raft-mimicking lipid mixtures. Biophys J 104, 2212-2221. scientist in the group of Prof. Lon- Iwabuchi K, Nakayama H, Iwahara C, Takamori K (2010). Significance of glycosphingolipid don (Stony Brook University, NY) where he developed a method fatty acid chain length on membrane microdomain-mediated signal transduction. FEBS Lett for the production of asymmetric giant lipid vesicles (GUVs). At 584, 1642-1652. Pautot S, Frisken BJ, Weitz DA (2003). Engineering asymmetric vesicles. Proc Natl Acad Sci U the present, he is holding a PostDoc position in the Department S A 100, 10718-10721. of Biology / A. Herrmann’s group at the HU Berlin, studying in- Rothman JE, Lenard J (1977). Membrane asymmetry. Science 195, 743-753. fluenza virus assembly. Simons K, Gerl MJ (2010). Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11, 688-699. Simons K, Ikonen E (1997). Functional rafts in cell membranes. Nature 387, 569-572. Son M, London E (2013). The dependence of lipid asymmetry upon phosphatidylcholine acyl chain structure. J Lipid Res 54, 223-231. Stefanova I, Horejsi V, Ansotegui IJ, Knapp W, Stockinger H (1991). GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254, 1016-1019. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Sci- ence 319, 1244-1247. Veit M, Thaa B (2011). Association of influenza virus proteins with membrane rafts. Adv Virol 2011, 370606. Wan C, Kiessling V, Tamm LK (2008). Coupling of cholesterol-rich lipid phases in asymmetric bilayers. Biochemistry 47, 2190-2198. Wang TY, Silvius JR (2001). Cholesterol does not induce segregation of liquid-ordered domains in bilayers modeling the inner leaflet of the plasma membrane. Biophys J 81, 2762-2773.

Cell News 3/2013 17 RESEARCH NEWS

On Spindle Length and Shape.

Simone Reber Max-Planck-Institute of Molecular Cell Biology and , Pfotenhauer Strasse 108, 01307 Dresden, www.simonereber.com

The internal organization of a cell is critical for its viability and plasma cells, each of which secretes thousands of antibodies per specifically tailored to its function. Therefore, number, size, and second. This massive Ig production correlates with an expansion geometry of intracellular organelles are important and must be of the ER4. As basic physiological processes such as molecular tightly regulated according to cell cycle state and cell type. A transport rates across membranes are intrinsically size-depen- classic example for the tight control of organelle number is the dent, their efficiency will vary with changes in organelle surface cycle. are the major microtubule-orga- area or volume5. Thus to understand cell organization, it will be nizing centre of animal cells and their number is linked to the critical to understand how cells sense and control the number, cell cycle state. In interphase, centrosome number is limited to size and shape of their organelles. one centrosome per cell. Before mitosis, centrosomes duplicate precisely once to become the poles of the bipolar mitotic spind- While approaching near to complete proteomic parts lists of cel- le1. Aberrant centrosome numbers can result in the generation lular structures and organelles, mechanisms that control their of abnormal mitotic spindles and thus be a source of chromoso- defined shape and size remain poorly understood. One reason me instability, a hallmark of cancer2. Examples of cells adjusting why this question has been so hard to answer is that the size of their internal organization are the active size regulation of the an organelle is generally not simply set by a “ruler” (Figure 1a) mitochondrial meshwork in muscle cells or the over-proliferation but is an emergent property of molecular collectives (Figure 1b). of the ER in secretory cells. Muscle cells can respond to chan- “Emergence” describes the way complex properties and patterns ges in energy demands by modifying the rates of mitochondrial of a system arise by numerous elements, which interact by rela- biogenesis to induce compensatory changes in mitochondrial tively simple rules. Examples include the generation of an infi- capacity3. B cells express immunoglobulins (Ig) on their surface nite variety of six-sided snowflakes from frozen water in snow6 but do not secrete antibodies. Upon binding of a specific antigen (Figure 1c). Similarly, “flocking”, the coordinated motion of ani- to the B cell receptor, B cells proliferate and differentiate into mals observed in bird flocks, fish schools, or insects swarms, is

Figure 1. Emergent Properties on Different Length Scales: a) Xenopus spindle length is not set by a “ruler” (a) but is a collective behaviour problem (b). (c) Snow crystal. Scale bar ~1 mm Image courtesy Kenneth G. Libbrecht (http://www.its.caltech.edu/~atomic/snowcrystals/). (d) Starling flock. Scale bar ~10 m. Image courtesy Robert Wolstenholme (http://www. robwolstenholme.co.uk/). (e) Metaphase spindle assembled in Xenopus egg extracts. Scale bar 10 µm.

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considered an emergent behaviour7 (Figure 1d). In physics emer- its overall geometry (Figure 2a). Mass balance, which is based gent behaviours are commonly studied to describe complex on the principle of mass conservation, is often used in physics systems. Physics thus provides a framework for relating the mi- and engineering to infer properties of systems that are difficult croscopic properties of individual molecules to the macroscopic to measure directly. In the 1940s, Irvin Isenberg suggested that properties of materials. This exactly is the key challenge in mo- the spindle might be a liquid crystal11. Indeed, more recent ob- dern cell biology, bridging the gap between individual molecules servations in Xenopus egg extracts imply that spindles can dis- and their collective behaviour (Figure 1e). play liquid-like properties. For example, two meiotic spindles fuse when brought close together12. Furthermore, micromanipu- A Multi-Scale Model for Xenopus Spindles Length. lation studies on Xenopus spindles show that spindles recover During early Xenopus development cell size decreases dramati- their original shape after weak compressions and that they have cally from a 1200 µm diameter fertilized egg to approximate- anisotropic material properties13-16. This coarse-grained “liquid ly 12 µm diameter blastomeres8. Consequently, the metaphase crystal” analogy has important implications, because spindle spindle needs to function in cell volumes that vary by several length follows from a simple book-keeping exercise based on orders of magnitude. Because defects in spindle length result in mass balance: The length of the spindle will simply depend on erroneous cell division9, robust mechanisms to set the length of the balance of material that is created (nucleation and assembly) a spindle and scale it according to cell type must exist. Deca- and lost (disassembly), while the density of microtubules remains des of work have shown that microtubule dynamics, nucleation, roughly constant. At steady-state, the rate of volume increase and transport are critical for spindle assembly10. However, the due to incorporation of tubulin into microtubules equals the rate combined activities of these processes, as well as their complex of volume loss due to microtubule disassembly. Consequently, interplay, make it difficult to determine how each individual pro- spindle length is ultimately related to the kinetic parameters of cess contributes to the overall organization of the spindle. microtubule nucleation, assembly and disassembly17 (Figure 2b).

We have recently shown that mass balance together with a “li- A key prediction of our work is that spindle length scales linear- quid crystal” analogy is a useful working hypothesis to account ly with microtubule growth velocity when other parameters of for the dynamic properties of Xenopus spindles and link these to spindle organization remain constant17. This prediction can be tested in quantitative experiments that allow the modulation of microtubule dynamics in Xenopus egg extract spindles. But how can we specifically modulate microtubule growth rates? Work over the last decade established a major role for XMAP215 in microtubule growth promotion. XMAP215 was shown to act as a processive microtubule polymerase that promotes incorporation of tubulin into the growing plus end (Figure 3a). XMAP215 binds the tubulin heterodimer in a 1:1 stoichiometry, ‘surfs’ the gro- wing microtubule plus end, and stays there for multiple rounds of tubulin incorporation18. XMAP215 was first isolated from Xe- nopus eggs19 and subsequently found in all major kingdoms of eukaryotes, including fungi (Stu220 in S. cerevisiae, Dis121 and Alp1422 in S. pombe), plants (Mor123 in A. thaliana) and animals (Zyg924 in C. elegans, mini spindles25 in D. melanogaster, and ch-TOG26 in humans). All members of the XMAP215 family are characterized by a varying number of TOG domains at their N- termini (Figure 3b). However, how these various domains contri- bute to XMAP215 activity was until recently not known. Based on mutants in TOG domains that interfere with tubulin binding27, it has been proposed that TOG binding to tubulin is required for its catalytic activity28; however, there was no proof for this idea.

Recently, we have shown that the polymerase activity of XMAP215 depends on tubulin binding to multiple TOG domains. Mutation of conserved residues in different TOG domains redu- ces tubulin binding while concomitantly reducing the maximal growth promoting activity of the polymerase (Figure 3c). Com- bining mutations in different TOG domains allowed us to mo- Figure 2. Xenopus Spindle Length: dulate the enzymatic activity of XMAP215 and thereby control (a) Mass balance together with a “liquid crystal” analogy allows us to rela- microtubule growth velocity in vitro 29. This set of well-charac- te kinetic parameters of microtubule nucleation, assembly and disassembly (b) and the overall geometry of Xenopus spindles. terized polymerase mutants served as an experimental tool kit

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Figure 3. Xenopus Spindle Length Is Directly Proportional to XMAP215 Microtubule Polymerase Activity: (a) XMAP215 acts as a processive polymerase. (b) Schematic of Xenopus laevis XMAP215’s domain structure indicating the point mutations introduced. (c) Tubulin affinity and maximal microtubule growth promoted by XMAP215 and the mutants. (d) Xenopus egg extract was MOCK or XMAP215 depleted, different point mutants of XMAP215 were added back. Depletion efficiency and accuracy of add-back were controlled by Western blot analysis, tubulin served as a loading control. (e) Spindles were assembled in the presence of different XMAP215 mutants. The upper rows show a representative spindle (red: microtubules, blue: DNA), the lower rows show an average image of all spindles from three independent experiments, the average spindle length is indicated. SE, n=40. Scale bars: 10 µm. (f) Average spindle length measured in the presence of different XMAP215 point mutants. Error bars indicate SE (n=40). (g) Spindle length plotted versus the maximal in vitro microtubule growth velocity promoted by different XMAP215 mutants. Grey areas indicate the 95% confidence intervals of the fitted curves. Adapted from17.

20 Cell News 3/2013 See like you have never seen before to fine-tune microtubule growth rates in Xenopus spindles. To implement this tool kit, we depleted the endogenous XMAP215 from Xenopus egg extracts (Figure 3d), added back the mutant polymerases and assembled spindles (Figure 3e). At endogenous concentration, all mutants promoted assembly of spindles at lengths proportional to their polymerase activity (Figure 3f). An alternative way to modified XMAP215 activity is adding back recombinant wildtype XMAP215 at different concentrations to XMAP215-depleted extracts. Similarly, spindle length increased with increasing wildtype XMAP215 concentrations. However, at some point adding more than XMAP215 did not result in longer spindles but spindle length plateaued, consistent with existing evidence for an upper limit to spindle length30. When we corre- lated spindle length with the maximum microtubule growth pro- motion, spindle length was directly proportional to the maximal growth promoted by XMAP215 (Figure 3g), exactly as predicted by our model.

Interestingly, we observed that spindle shape remains cons- tant while spindle length changes significantly with varying XMAP215 activities17. This is surprising and suggests that shape is determined by distinct mechanisms that are independent from those determining length. From a developmental or scaling point of view, the separation of length and shape is appealing as it allows fine-tuning of spindle length without changing its overall morphology. We thus propose that force balances set the shape of the metaphase spindle. Nevertheless, it remains to be shown experimentally which forces shape the metaphase spindle and to characterize the molecular factors that underlie these forces.

To conclude, our molecular understanding of XMAP215 has allo- wed us to perform a “synthetic biology” experiment, in which we can limit the length of a spindle solely by using an appropriate, engineered mutant. Combining experiments and theory has allo- wed us to bridge scales from the level of single microtubule dy- namics to the overall organization of the spindle by using mass balance. Many manipulations of microtubule dynamics alter the size and shape of the spindle in a variety of systems31-36. Our mo- del provides a conceptual framework for understanding why per- turbations in microtubule dynamics often result in spindle length changes. Any modulation that solely affects a single parameter of spindle organization will change the mass balance and thus result in changes in spindle length.

Material Properties and Organelle Scaling. Our experiments suggest that Xenopus spindles join a growing number of cellular structures that can be treated as active li- Ÿ Zoomweltmeister 25:1 quids. One example are RNA/protein complexes of P granules in C. elegans that were shown to exhibit liquid-like behaviours, Ÿ Sensationelle Auflösung: 1100 LP/mm which suggest a simple physical picture for P granule localizati- Ÿ Vollständige Ergonomie on37. Likewise, nucleoli in amphibian oocyte behave like liquid- like droplets38. Only recently, the centrosome was suggested Ÿ Stark verbesserte Fluoreszenz to be an autocatalytic drop, which explains the formation of Ÿ centrosomes only around and their scaling with cell Hellere Bilder und höherer Kontrast size (Zwicker et al., unpublished and 39). One characteristic of all these highly dynamic structures is that they are non-membrane www.nikoninstruments.com Nikon GmbH - Tiefenbroicher Weg 25 - 40472 Düsseldorf - Germany Tel.: 0211/9414 214 - Fax: 0211/9414 322 - E-Mail: [email protected] RESEARCH NEWS

bound and that their components are in constant exchange with gans protein required for microtubule organization and function, is a component of meiotic and mitotic spindle poles. J Cell Biol 141, 1159–1168 (1998). the surrounding cytoplasm. These biophysical studies are con- 25. Cullen, C. F., Deak, P., Glover, D. M. & Ohkura, H. mini spindles: A gene encoding a con- sistent with the emerging concept that phase separation is an served microtubule-associated protein required for the integrity of the mitotic spindle in important physical principle for organizing the internal structu- Drosophila. J Cell Biol 146, 1005–1018 (1999). 40 26. Charrasse, S. et al. The TOGp protein is a new human microtubule-associated protein res of cells . In the context of our studies, we can thus think of homologous to the Xenopus XMAP215. J Cell Sci 111 ( Pt 10), 1371–1383 (1998). a spindle as an active liquid crystal drop that is phase separated 27. Al-Bassam, J., Larsen, N. A., Hyman, A. A. & Harrison, S. C. Crystal structure of a TOG do- from the cytoplasm. In this case, the formation of the second main: conserved features of XMAP215/Dis1-family TOG domains and implications for tubulin binding. Structure 15, 355–362 (2007). phase is initiated by chromatin, which induces local nucleation 28. Ovechkina, Y., Wagenbach, M. & Wordeman, L. K-loop insertion restores microtubule of microtubules. While the microtubule phase is forming, other depolymerizing activity of a ‘neckless’ MCAK mutant. J Cell Biol 159, 557–562 (2002). components can segregate into this phase where they can mo- 29. Widlund, P. O. et al. XMAP215 polymerase activity is built by combining multiple tu- bulin-binding TOG domains and a basic lattice-binding region. Proceedings of the National dulate spindle assembly, dynamics, and shape. Academy of Sciences 108, 2741–2746 (2011). 30. Wuehr, M. et al. Evidence for an upper limit to mitotic spindle length. Current Biology Acknowledgments 18, 1256–1261 (2008). 31. Budde, P. P., Kumagai, A., Dunphy, W. G. & Heald, R. Regulation of Op18 during spindle I thank all the present and past members of the Hyman lab, and assembly in Xenopus egg extracts. J Cell Biol 153, 149–158 (2001). my colleagues at the MPI-CBG and MPI-PKS. My work was sup- 32. Gaetz, J. Dynein/dynactin regulate metaphase spindle length by targeting depolymeri- ported by the European Commission's 7th Framework Program- zing activities to spindle poles. J Cell Biol 166, 465–471 (2004). 33. Goshima, G. et al. Genes required for mitotic spindle assembly in Drosophila S2 cells. me grant Systems Biology of Stem Cells and Reprogramming Science 316, 417–421 (2007). (HEALTH-F7-2010-242129/SyBoSS). 34. Bird, A. W. & Hyman, A. A. Building a spindle of the correct length in human cells requi- res the interaction between TPX2 and Aurora A. J Cell Biol 182, 289–300 (2008). 35. Brust-Mascher, I., Sommi, P., Cheerambathur, D. 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22 Cell News 3/2013 Special intereSt Meeting Seminaris SeeHotel potsdam, germany June 10 – 13, 2014

mOLeCuLar insigHt intO musCLe funCtiOn and prOtein aggregate myOpatHies

Organizers Dieter O. Fürst, University of Bonn | Harald Herrmann, DKFZ Heidelberg rolf Schröder, University Hospital erlangen speakers COnfirmed Dietmar Manstein, Hannover Ueli aebi, Basel Katrin Marcus, Bochum giselle Bonne, paris Jennifer e. Morgan, london thomas Braun, Bad nauheim anders Oldfors, gothenburg Folma Buss, cambridge gabriella piazzesi, Sesto Fiorentino Yassemi capetanaki, athens roy Quinlan, Durham gloria conover, college Station Matthias rief, München Kristina Djinovi-carugo, Vienna Wolfgang rottbauer, Ulm elisabeth ehler, london Marco Sandri, padova peter gunning, Sydney Omar Skalli, Memphis rudolf a. Kley, Bochum theresia Stradal, Münster leslie leinwand , Boulder thomas Voit, paris Wolfgang linke, Bochum gerhard Wiche, Vienna meeting OrganizatiOn annika Bleckert, Legal Organizer (pCO) – mCi deutschland gmbH [email protected] abstract submission deadline: february 28, 2014 registration deadline: april 30, 2014 www.musclepam2014.de FUTURE MEETING

Special Interest Meeting of the German Society for Cell Biology: "Molecular Insight into Muscle Function and Protein Aggregate Myopathies"

June 10 – 13, 2014 Seminaris SeeHotel, Potsdam, Germany

Organized by Dieter O. Fürst (University of Bonn) | Harald Herrmann (German Cancer Research Center, Heidelberg) | Rolf Schröder (University Hospital Erlangen)

Recent years have yielded a vast amount of novel and fundamental insight into the molecular basis of striated muscle development and function as well as the pathogenesis of neuromuscular and cardiac diseases. Protein aggregate myopathies (PAM) are an emer- ging and numerically significant group of hereditary and acquired striated muscle diseases with marked clinical and genetic hetero- geneity. Exciting novel insight into the molecular pathogenesis of PAM lead to concepts in which PAM-related gene defects cause effects at multiple levels by influencing the structure and function of motor proteins, sarcomeric and extra-sarcomeric cytoskeleton proteins, signaling cascades, protein quality control systems as well as the function of cell organelles in striated muscle cells. This enormous progress has been achieved by work in a wide variety of specialized basic and clinical scientific disciplines. However, the conversion of basic science and clinical findings remains a major challenge. This meeting aims at promoting a multidisciplinary di- alogue between experts in the field of muscle research with basic scientific and clinical backgrounds that cover biophysics, protein biochemistry, genetics, cell biology, physiology, myopathology and clinical neurology. In addition, advanced experimental approaches in muscle research and novel therapeutic strategies for the treatment of hereditary myopathies and cardiomyopathies will be high- lighted.

The main topics of the meeting are Motor and Cytoskeleton Proteins in Normal and Diseased Muscle Protein Quality Control Protein Aggregate Myopathies Advanced Experimental Approaches

Registration fee (including accomodation and all meals!) 650,- for scientists 600,- for scientists who are DGZ members 550,- for students 500,- for students who are DGZ members

The number of participants is limited. All participants are invited to submit an abstract to apply for a short talk (limited number only!) and/or poster contribution.

Application deadline: February 28, 2014

Please visit for further information and registration: www.musclepam2014.de

24 Cell News 3/2013 FUTURE MEETING

Tuesday, June 10th, 2014 17:00 – 19:00 Opening Lectures Keynote Lecture 1: Thomas Braun (Bad Nauheim, Germany): Regenerative capacity of striated muscle tissue Keynote Lecture 2: Leslie Leinwand (Boulder, USA): Molecular basis of inherited cardiomyopathies 20:00 Dinner and get together

Wednesday, June 11th, 2014 Session 1: Intermediate Filaments 8:30 Gisèle Bonne (Paris, France): Lamin A/C myopathies: molecular insight from cell and animal models 9:00 Omar Skalli (Memphis, USA): The role of synemin in normal and diseased muscle 9:30 Yassemi Capetanaki (Athens, Greece): Myospryn: a multi-functional protein associated with desmin 10:00 talks selected from Abstracts 10:30 Coffee and Discussion Session 2: IF-Associated Proteins 11:00 Gerhard Wiche (Vienna, Austria): Plectinopathies: from cell and animal models to the evaluation of treatment strategies 11:30 Gloria Conover (Galveston, USA): Nebulin – getting it clear with desmin 12:00 talks selected from Abstracts 13:00 Lunch Break 14:00-15:30 Poster Session I with Coffee and Discussion Session 3: Protein quality control 15:30 Roy Quinlan (Durham, UK): The functional role of B-crystalline for muscle maintenance 16:00 Wolfgang Rottbauer (Ulm, Germany): VCP & VCP binding partners: lesson from functional genomics in zebrafish 16:30 Marco Sandri (Padova, Italy): Regulation of the autophagic system in striated muscle waisting 17:00 talks selected from Abstracts 18:30 Dinner 20:00 After-Dinner-Talk Ueli Aebi (Biozentrum Basel) Actin: from Structural Plasticity to Functional Diversity

Thursday, June 12th, 2014 Session 4: Motor proteins 8:30 Jennifer Morgan (London, UK): Mouse muscle stem cells: Different satellite cells? 9:00 Folma Buss (Cambridge, UK): The role of myosins in autophagy 9:30 Theresia Stradal (Braunschweig, Germany): Molecular regulation of actin-based cellular protrusions 10:00 Dietmar Manstein (Hannover, Germany): From molecular structure to the pathophysiology of motor protein-linked diseases 10:30 Peter Gunning (Sydney, Australia): Actin- and tropomyosin-associated myopathies 11:00 Coffee and Discussion Session 5: Titin 11:30 Wolfgang Linke (Bochum, Germany): Titin and its role in cell signalling 12:00 Anders Oldfors (Gothenburg, Sweden): Clinic, genetic and pathiophysiological aspects of HMERF 12:30 talks selected from Abstracts 13:00 Lunch Break 14:00 – 15:30 Poster Session II with Coffee and Discussion Session 6: Filamin C 15:30 Rudolf Kley (Bochum, Germany): Proteomic profiles in myofibrillar myopathies 16:00 talks selected from Abstracts 17:00 Coffee and Discussion 17:30 - 18:30 Highlights from the Posters (Chair: Harald Herrmann) 18:30 - 19:30 Plenary talk: Matthias Rief (Munich, Germany): Mechanics of single molecules 20:00 Social event FUTURE MEETING

Friday, June 13th, 2014 Session 7: Advanced Experimental Approaches 8:30 Elisabeth Ehler (London, Germany): A central role of the intercalated disc for cardiomyocyte growth 9:00 Gabriella Piazzesi (Florence, Italy): Force sensing in muscle 9:30 talks selected from Abstracts 10:00 Coffee and Discussion 10:30 Katrin Markus (Bochum, Germany): Quantitative Methods in Proteomics 11:00 Kristina Djinovi -Carugo (Vienna, Austria): Lessons from integrative structural biology 11:30 talk selected from Abstracts 12:00 Plenary talk: Thomas Voit (Paris, France): Recent advances of gene therapy approaches in neuromuscular disorders 13:00 Departure

www.musclepam2014.de

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www.hamamatsu.com 26 Cell News 3/2013 INTERN

The DGZ welcomes the following new members:

Impressum Prof. Dr. Thomas Dresselhaus Dr. Stefanie Redemann Publisher: Deutsche Gesellschaft für Prof. Dr. Dorothea Schulte Zellbiologie e.V. (DGZ) (German Society for Cell Biology) Missing members: Editor-in-Chief: Harald Herrmann We have no valid address from the members listed below. If anybody can help us in this respect, please send a message to the DGZ office at [email protected]. Editorial Board: Ralph Gräf Ludwig Eichinger Stephan Adelt Giselbert Hinz Stephan Peter Oliver Gruss Friedemann Kiefer Marwan Al Falah Christa Hochhuth Kirsten Peters Thomas Magin Jens Altrichter Jan Hönnemann Winfried Peters

Every article stands in the responsibility of the author. Dorit Arlt Christine Hoffmann Alexander Petrovitch For unsolicited sent manuscripts the society does not undertake liability. Reproduction, also in part, only Jennifer Baltes Thomas Jarchau Johannes Pohlner with permission of the society and with reference. Tanja Barendziak Günter Kahl Eduard Resch Editorial Office Friederike Bathe Antje Kettelhake Filomena Ricciardi Manuscripts/Advertisements: Sabine Reichel-Klingmann Manuel Bauer Erich Knop Astrid Riehl Office of the German Society Wolfgang Bielke Victoria Kolb-Bachofen Oliver Rößler for Cell Biology Jessica Blume Karl-Hermann Korfsmeier Josef Rüschoff c/o German Cancer Research Center Im Neuenheimer Feld 280 Peter Brandt Martina Kralewski Wilhelm Sachsenmaier 69120 Heidelberg Theo Brigge Bernd Krüger Klaus-Dieter Scharf Tel.: 06221/42-3451 Fax: 06221/42-3452 Andreas Brown Ralf Kuchenbecker Timo Schinköthe E-mail: [email protected] Julia Bubeck Christian Kutzleb Katharina Schönrath Internet: www.zellbiologie.de Winfried Busch Philipp Lange Daniela Schreiber Production: Stacy Carl-McGrath Gilbert Lauter Gerd Schwarz abcdruck GmbH Waldhofer Str. 19 · 69123 Heidelberg Rüdiger Cerff Friederike Lehmann Udo Seedorf E-mail: [email protected] Philip Dannhauser Joern Linkner Klaus Seidl Web: www.abcdruck.de Ulrich Drews Sabine März Jamal Souady Media Creation: Hans-Georg Eckert Anne Meinzinger Karsten Spring Anna Wagner Michael F. Trendelenburg E-mail: [email protected] Danai Feida Elena Motrescu Michael Fredrich Günter Müller Nadime Ünver Full electronic version Christiane Gerlach Jens Müller Jürgen Voigt Frequency of publication: Horst Hameister Thomas Noll Wibke Wagner 4 issues yearly Kristina Hartmann Tobias Ölschläger Diego J. Walther If you are interested in advertising, Detlev Herbst Adaling Ogilvie Shuoshuo Wang please contact the DGZ office ([email protected]) Michael Hilker Andrea Pauli Christiane Weydig Anna-Lena Hillje Gerd Paulus

Cell News 3/2013 27 Life at the Edge: The Nuclear Envelope in Nucleocytoplasmic Transport, Genome Organization and Cell Cycle Regulation International Meeting of the German Society for Cell Biology (DGZ) CONFIRMED SPEAKERS Wolfram Antonin Potsdam, July 23-26, 2014 Tübingen Seminaris Seehotel Potsdam Peter Askjaer Sevilla Martin Beck Heidelberg ORGANIZERS Günter Blobel New York Birthe Fahrenkrog Yuh Min Chook Dallas Université Libre de Bruxelles Valérie Doye Ralph Kehlenbach Paris Universität Göttingen Roland Foisner Wien Susan Gasser Basel

REGISTRATION Pierre-Emmanuel Gleizes deadline 2 June 2014 Toulouse ABSTRACT submission Dirk Görlich deadline 2 May 2014 Göttingen Ed Hurt www.zellbiologie.de Heidelberg Naoko Imamoto Saitama Ulrich Kubitscheck Bonn Ulrike Kutay Zürich

Mike Rout CONTACT New York [email protected] Thomas Schwartz [email protected] Boston Irina Solovei München Bas van Steensel Amsterdam Susan Wente

sdam Nashville Pot äf, Gr Ralph by aphy

photogr additional speakers will be selected from the abstracts