Prof. Dr. Sander van den Heuvel
Our research focuses on the coordinated regulation of cell division and differentiation in the context of animal development. Our goal is to obtain a deeper understanding, at the molecular and systems level, of the mechanisms that control two important developmental decisions:
- The decision to undergo either proliferative or asymmetric cell division.
- The choice between continued cell division and terminal differentiation.
A human body consists of an estimated hundred trillion cells, of which a substantial fraction needs to be renewed every day. This makes cell division, and the balance between cell proliferation and differentiation, key aspects of normal development and health. Successful cell division requires coordination between chromosome segregation and cytoplasmic cleavage and leads to the formation of two daughter cells with the same genome. However, such daughter cells may differ in inherited constituents and signals they receive, and as a consequence take on different developmental fates.
Cell divisions that generate identical daughter cells and promote exponential increases in cell numbers are considered “proliferative” divisions. In contrast, asymmetric cell divisions often segregate the potential to proliferate and the commitment to differentiate to different daughter cells. This supports the maintenance of stable numbers of proliferating cells and promotes the generation of cell diversity. The difference in daughter cell fate may be achieved during the division process (intrinsically asymmetric division) or be acquired after division through external signals that are often derived from a niche. Adult stem- and precursor cells use one of these forms of asymmetric cell division to combine self-renewal with the production of differentiated daughter cells.
Clearly, the balance between proliferative and asymmetric cell divisions is crucial in the formation of the proper cell types and cell numbers during development and tissue homeostasis. Our goal is to obtain a deeper fundamental understanding of the molecular and systemic regulation of cell division in concert with differentiation. These studies start from a genetic model system, yet aim to contribute to a deeper understanding of human development and tissue regeneration, and to add improved insights in how disrupted proliferation/differentiation contributes to cancer and developmental abnormalities.
Our model system
The nematode Caenorhabditis elegans offers a powerful model system to study cell division control during animal development. These animals have a transparent body and develop from the one-cell zygote to adult stage through a nearly invariant pattern of divisions. Thus, the division of all somatic cells can be followed within the developing animals and the exact times of cell division are known (Sulston et al; Dev. Biol. 1978, 1980). In combination with efficient genetics, this allows for a sensitive identification of cell cycle mutants and quantitative analysis of cell-division defects at a resolution that exceeds the possibilities in other animal models. Moreover, cells in the early embryo are large and the chromosomes and spindle asters cytologically observable, which are attractive aspects for cell biology and live imaging based approaches. Given the observed conservation of cell division processes and developmental pathways, C. elegans has the potential for major contributions towards understanding the coordination between cell division and differentiation in animal development.
Understanding the complex and dynamic regulation of cell proliferation and differentiation in development requires a multi-disciplinary approach. While much of our work is based on observations in vivo, we combine genetics and in vivo imaging in the nematode Caenorhabditis elegans with gene-expression profiling, mass spectrometry analysis, yeast two-hybrid studies, and experiments with cells in culture. In addition, we have recently started to include mathematical modeling and computer simulation in our studies of asymmetric cell division, in collaboration with the theoretical biology department at Utrecht University.
- Molecular mechanisms of asymmetric cell division
- Control of stem cell divisions in the C. elegans epidermis
- The Proliferation/Differentiation Decision
- Control of the G1-to-S-phase transition
- Developmental control of cell-cycle entry
- Developmental control of cleavage plane specification
Current lab members:
- Suzanne van der Horst (Ph.D. student)
- Vincent Portegijs (Ph.D. student)
- Ruben Schmidt (Ph.D. student)
- Lars-Eric Fielmich (Ph.D. student)
- Juliane Teapal (Research technologist & core facility manager)
- Janine Anselmo Cravo (Ph.D. student)
- Molly Godfrey (Postdoctoral fellow)
- Amir Homavar (Ph.D. student)
Former lab members:
- Aniek van der Vaart (Postdoctoral fellow)
- Herman van der Klis (Research technician)
- Suzan Ruijtenberg (Ph.D. student)
- Marjolein Wildwater (Postdoc)
- Christian Berends (Ph.D. student)
- Tim van Mourik (Ph.D. student)
- Matilde Galli (Ph.D. student)
- Jerome Korzelius (Ph.D. student)
- Julian Ceron (Postdoc)
- Mako Saito (Postdoc)
- Monique Lorson (Postdoc)
- Dayalan Srinivasan (Ph.D. student)
- Mike Boxem (Ph.D. student)
- Ridgely Fisk (Ph.D. student)
- Attila Stetak (Postdoc)
- Monique van der Voet (Ph.D. student)
- Abha Chandra (Postdoc)
- John Koreth (Postdoc)
- Huihong Xu (Research technician)
- Audrey Perreault (Research technician)
Fielmich LE, Schmidt R, Dickinson DJ, Goldstein B, Akhmanova A, Van den Heuvel S Optogenetic dissection of mitotic spindle positioning in vivo 2018 Aug 15 Elife
Sugioka K, Fielmich LE, Mizumoto K, Bowerman B, van den Heuvel S, Kimura A, Sawa H Tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division Proc Natl Acad Sci USA 2018 Jan 30
Schmidt R, Fielmich LE, Grigoriev I, Katrukha EA, Akhmanova A, van den Heuvel S Two populations of cytoplasmic dynein contribute to spindle positioning in C. elegans embryos J Cell Biol. 2017 Jul 24
van Rijnberk LM, van der Horst SE, van den Heuvel S, Ruijtenberg S. A dual transcriptional reporter and CDK-activity sensor marks cell cycle entry and progression in C. elegans.a> PLoS ONE 2017 Feb 12(2)
Portegijs V, Fielmich LE, Galli M, Schmidt R, Muñoz J, van Mourik T, Akhmanova A, Boxem M van den Heuvel S Multisite Phosphorylation of NuMA-Related LIN-5 Controls Mitotic Spindle Positioning in C. elegans. PloS Genetics 2016 Oct 6;12(10)
Van der Vaart A, van den Heuvel S Switching on regeneration. Stem Cell Investigation. 2016;3:41
Waaijers S, Muñoz J, Berends C, Ramalho JJ, Goerdayal SS, Low TY, Zoumaro-Djayoon AD, Hoffmann M, Koorman T, Roderick PT, Harterink M, Seelk S, Kerver J, Hoogenraad CC, Bossinger O, Tursun B, van den Heuvel S, Heck AJR, Boxem M A tissue-specific protein purification approach in Caenorhabditis elegans identifies novel interaction partners of DLG-1/Discs large. BMC Biology 2016 Aug; 14:66
Akhmanova A and van den Heuvel S Tipping the spindle into the right position. JCB. 2016 May;213:293-95.
Koorman T, Klompstra D, van der Voet M, Lemmens I, Ramalho JJ, Nieuwenhuize S, van den Heuvel S, Tavernier J, Nance J, Boxem M. A combined binary interaction and phenotypic map of C. elegans cell polarity proteins. Nat Cell Biol.. 2016 Mar;18(3):337-46.
Harterink M, van Bergeijk P, Allier C, de Haan B, van den Heuvel S, Hoogenraad CC, Kapitein LC. Light-controlled intracellular transport in Caenorhabditis elegans. Curr Biol.. 2016 Feb 22;26(4):R153-4.
Ruijtenberg S, van den Heuvel S. Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression. Cell Cycle. 2016 Jan 17;15(2):196-212.
Ruijtenberg S, van den Heuvel S. G1/S Inhibitors and the SWI/SNF Complex Control Cell-Cycle Exit during Muscle Differentiation. Cell. 2015 Jul 16;162(2):300-13.
van Schendel R, Roerink SF, Portegijs V, van den Heuvel S, Tijsterman M. Polymerase Θ is a key driver of genome evolution and of CRISPR/Cas9-mediated mutagenesis. Nat. Commun. 2015 Jun 16;6:7394.
Maia AF, Tanenbaum ME, Galli M, Lelieveld D, Egan DA, Gassmann R, Sunkel CE, van den Heuvel S, Medema RH. Genome-wide RNAi screen for synthetic lethal interactions with the C. elegans kinesin-5 homolog BMK-1. Sci. Data. 2015 May 12;2:150020.
The I, Ruijtenberg S, Bouchet BP, Cristobal A, Prinsen MB, van Mourik T, Koreth J, Xu H, Heck AJ, Akhmanova A, Cuppen E, Boxem M, Muñoz J, van den Heuvel S. Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells. Nat. Commun. 2015 Jan 6;6:5906.
Fielmich L-E and Van den Heuvel S. Polarity Control of Spindle Positioning in the C. elegans Embryo. In: Cell Polarity in Development and Disease (Volume 2) Springer, Editor: Klaus Ebnet.
Waaijers S, Portegijs V, Kerver J, Lemmens BB, Tijsterman M, van den Heuvel S, Boxem M. CRISPR/Cas9-Targeted Mutagenesis in Caenorhabditis elegans. Genetics. 2013 Aug 26.
Berends CW, Muñoz J, Portegijs V, Schmidt R, Grigoriev I, Boxem M, Akhmanova A, Heck AJ, van den Heuvel S. F-actin asymmetry and the endoplasmic reticulum-associated TCC-1 protein contribute to stereotypic spindle movements in the Caenorhabditis elegans embryo. Mol Biol. Cell 2013 Jul;24(14):2201-15.
Van den Heuvel S, Kipreos ET. C. elegans cell cycle analysis. Methods Cell Biol. 2012 107:265-94.
Korzelius J, The I, Ruijtenberg S, Prinsen MB, Portegijs V, Middelkoop TC, Groot Koerkamp MJ, Holstege FC, Boxem M, van den Heuvel S. Caenorhabditis elegans cyclin D/CDK4 and cyclin E/CDK2 induce distinct cell cycle re-entry programs in differentiated muscle cells. PLoS Genet. 2011 Nov;7(11)
Wildwater M, Sander N, de Vreede G, van den Heuvel S. Cell shape and Wnt signaling redundantly control the division axis of C. elegans epithelial stem cells. Development. 2011 Oct;138(20):4375-85.
Galli M, Muñoz J, Portegijs V, Boxem M, Grill SW, Heck AJ, van den Heuvel S. aPKC phosphorylates NuMA-related LIN-5 to position the mitotic spindle during asymmetric division. Nat. Cell Biol. 2011 Aug 21;13(9):1132-8.
Korzelius J, The I, Ruijtenberg S, Portegijs V, Xu H, Horvitz HR, van den Heuvel S. C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability. Dev. Biol. 2011 Feb 15;350(2):358-69.
Ruijtenberg S, van den Heuvel S, The I. Regulation of DNA synthesis and replication checkpoint activation during C. elegans development. InTech Open Access Books. Edited by Jelena Kusic-Tisma. 2011 Sep. ISBN 978-953-307-775-8
Kops GJ, van der Voet M, Manak MS, van Osch MH, Naini SM, Brear A, McLeod IX, Hentschel DM, Yates JR 3rd, van den Heuvel S, Shah JV. APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome. J. Cell Sci. 2010 May 15;123(Pt 10):1623-33.
van der Voet M, Lorson MA, Srinivasan DG, Bennett KL, van den Heuvel S. C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation. Cell Cycle. 2009 Dec 15;8(24):4091-102.
Stetak A, Hörndli F, Maricq AV, van den Heuvel S, Hajnal A. Neuron-specific regulation of associative learning and memory by MAGI-1 in C. elegans. PLoS One. 2009 Jun 24;4(6):e6019.
van der Voet M, Berends CW, Perreault A, Nguyen-Ngoc T, Gönczy P, Vidal M, Boxem M, van den Heuvel S. NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Gα. Nat. Cell Biol. 2009 Mar;11(3):269-77.
van den Heuvel S, Dyson NJ. Conserved functions of the pRB and E2F families. Nat. Rev. Mol. Cell Biol. 2008 Sep;9(9):713-24.
Galli M, van den Heuvel S. Determination of the cleavage plane in early C. elegans embryos. Annu. Rev. Genet. 2008 Vol. 42:389-411.
Boxem M, Maliga Z, Klitgord N, Li N, Lemmens I, Mana M, de Lichtervelde L, Mul JD, van de Peut D, Devos M, Simonis N, Yildirim MA, Cokol M, Kao HL, de Smet AS, Wang H, Schlaitz AL, Hao T, Milstein S, Fan C, Tipsword M, Drew K, Galli M, Rhrissorrakrai K, Drechsel D, Koller D, Roth FP, Iakoucheva LM, Dunker AK, Bonneau R, Gunsalus KC, Hill DE, Piano F, Tavernier J, van den Heuvel S, Hyman AA, Vidal M. A protein domain-based interactome network for C. elegans early embryogenesis. Cell. 2008 Aug 8;134(3):534-45.
Clayton JE, van den Heuvel SJ, Saito RM. Transcriptional control of cell-cycle quiescence during C. elegans development. Dev. Biol. 2008 Jan 15;313(2):603-13.
Korzelius J, van den Heuvel S. Replication licensing: oops! ... I did it again. Curr. Biol. 2007 Aug 21;17(16):R630-2.
Wildwater M, The I, van den Heuvel S. Coordination of cell proliferation and differentiation: finding a GEM in the root? Dev. Cell. 2007 Jun;12(6):841-2.
Ceron J, Rual JF, Chandra A, Dupuy D, Vidal M, van den Heuvel S. Large-scale RNAi screens identify novel genes that interact with the C. elegans retinoblastoma pathway as well as splicing-related components with synMuv B activity. BMC Dev. Biol. 2007 Apr 6;7:30.
Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006 Aug 10;442(7103):700-4.
Shirayama M, Soto MC, Ishidate T, Kim S, Nakamura K, Bei Y, van den Heuvel S, Mello CC. The Conserved Kinases CDK-1, GSK-3, KIN-19, and MBK-2 Promote OMA-1 Destruction to Regulate the Oocyte-to-Embryo Transition in C. elegans. Curr. Biol. 2006 Jan 10;16(1):47-55.
van den Heuvel S. Cell-cycle regulation. WormBook. 2005 Sep 21:1-16.
Koreth J, van den Heuvel S. Cell-cycle control in Caenorhabditis elegans: how the worm moves from G1 to S. Oncogene. 2005 Apr 18;24(17):2756-64.
van den Heuvel S. The C. elegans cell cycle: overview of molecules and mechanisms. Methods Mol. Biol. 2005 Vol. 296:51-67.
Rual JF, Ceron J, Koreth J, Hao T, Nicot AS, Hirozane-Kishikawa T, Vandenhaute J, Orkin SH, Hill DE, van den Heuvel S, Vidal M. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 2004 Oct;14(10B):2162-8.
Miley GR, Fantz D, Glossip D, Lu X, Saito RM, Palmer RE, Inoue T, Van Den Heuvel S, Sternberg PW, Kornfeld K. Identification of residues of the Caenorhabditis elegans LIN-1 ETS domain that are necessary for DNA binding and regulation of vulval cell fates. Genetics. 2004 Aug;167(4):1697-709.
Saito RM, Perreault A, Peach B, Satterlee JS, van den Heuvel S. The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans. Nat. Cell Biol. 2004 Aug;6(8):777-83.
Zhang H, Christoforou A, Aravind L, Emmons SW, van den Heuvel S, Haber DA. The C. elegans Polycomb gene sop-2 encodes an RNA binding protein. Mol. Cell. 2004 Jun 18;14(6):841-7.
Fisk Green R, Lorson M, Walhout AJ, Vidal M, van den Heuvel S. Identification of critical domains and putative partners for the Caenorhabditis elegans spindle component LIN-5. Mol. Genet. Genomics. 2004 Jun;271(5):532-44.
Zhang H, Smolen GA, Palmer R, Christoforou A, van den Heuvel S, Haber DA. SUMO modification is required for in vivo Hox gene regulation by the Caenorhabditis elegans Polycomb group protein SOP-2. Nat. Genet. 2004 May;36(5):507-11.
van den Heuvel S. Protein degradation: CUL-3 and BTB—partners in proteolysis. Curr. Biol. 2004 Jan 20;14(2):R59-61.
*Li S, *Armstrong CM, *Bertin N, *Ge H, *Milstein S, *Boxem M, *Vidalain PO, *Han JD, *Chesneau A, Hao T, Goldberg DS, Li N, Martinez M, Rual JF, Lamesch P, Xu L, Tewari M, Wong SL, Zhang LV, Berriz GF, Jacotot L, Vaglio P, Reboul J, Hirozane-Kishikawa T, Li Q, Gabel HW, Elewa A, Baumgartner B, Rose DJ, Yu H, Bosak S, Sequerra R, Fraser A, Mango SE, Saxton WM, Strome S, Van Den Heuvel S, Piano F, Vandenhaute J, Sardet C, Gerstein M, Doucette-Stamm L, Gunsalus KC, Harper JW, Cusick ME, Roth FP, Hill DE, Vidal M. A map of the interactome network of the metazoan C. elegans. Science. 2004 Jan 23;303(5657):540-3.
*These authors contributed equally
Van den Heuvel S. The C. elegans cell cycle: overview of molecules and mechanisms. In: Methods in Molecular Biology. Edited by G Brooks and T Humphry, Humana Press, Inc. 2004 Vol 296, Cell Cycle Control, Mechanisms and Protocols. 51-67
Srinivasan DG, Fisk RM, Xu H, van den Heuvel S. A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C elegans. Genes Dev. 2003 May 15;17(10):1225-39.
Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC, Reynolds P, Bell DW, Lake R, van den Heuvel S, Settleman J, Haber DA. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell. 2003 Mar 7;112(5):673-84.