Developmental Biology

Mike Boxem, Ph.D.

Utrecht University
Kruytgebouw O508
Padualaan 8
3584 CH  Utrecht
The Netherlands

Phone: +31 (0)30 253 3714
Fax:  +31 (0)30 251 3655
m.boxem*at*uu.nl

Research summary

We study the molecular mechanisms that underlie cell polarity using a combination of high-throughput protein interaction mapping approaches and in vivo studies using the model organism C. elegans. Cell polarity is critical to animal development and tissue functioning, and defects in polarity are an important factor in the development of cancer and other diseases. Polarization of cells and tissues requires assembly of a variety of protein complexes that include scaffolding proteins with multiple protein binding domains. Identifying which proteins interact and how they interact is therefore an excellent starting point to improve our understanding of polarity establishment.

To systematically identify the protein interactions made by polarity regulators, we use two complementary technologies: the yeast two-hybrid (Y2H) system and affinity purification followed by mass spectrometry (AP/MS). Y2H identifies direct interactions between pairs of proteins (binary interactions), while AP/MS identifies members of stable complexes. By combining both technologies, a more comprehensive view of protein interactions is obtained. We are actively improving both technologies, for example by modifying the Y2H system to identify protein interaction domains, and by developing efficient AP/MS approaches for use in C. elegans.

To test novel hypotheses and candidate polarity proteins derived from the interactions identified, we make use of several polarity models available for C. elegans. Polarity of embryonic and post-embryonic tissues can be examined in live animals using fluorescently labeled proteins that are asymmetrically distributed or visualize components such as membranes, cell junctions, or the mitotic spindle. In combination with gene inactivation by RNA interference or mutations, these models allow us to examine the role of individual proteins in cell polarity in the context of a living, multicellular organism.

Research topics

• Cell polarity
  
• Protein interaction mapping
• C. elegans

People

Current lab members:

• Thijs Koorman (Ph.D. student)
• Selma Waaijers (Ph.D. student)
• Jana Kerver-Stumpfova (Research technician)
• Elizabeth Moustakidou (Master's degree student)

Former lab members:

• Monique van der Voet (Postdoc)
• Geert de Vreede (Master's degree student)
• Tanya Vermaas (Master's degree student)

Selected Publications

(The titles link to PubMed)

2011

Korzelius J, The SI, Ruijtenberg S, Prinsen M, Portegijs V, Middelkoop T, Groot Koerkamp MJ, Holstege FCP, Boxem M, and van den Heuvel S. C. elegans Cyclin D/Cdk4 and Cyclin E/Cdk2 Induce Distinct Cell Cycle Re-entry Programs in Differentiated Muscle Cells. PLoS Genetics 2011 in press

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.

Mukhtar MS, Carvunis AR, Dreze M, Epple P, Steinbrenner J, Moore J, Tasan M, Galli M, Hao T, Nishimura MT, Pevzner SJ, Donovan SE, Ghamsari L, Santhanam B, Romero V, Poulin MM, Gebreab F, Gutierrez BJ, Tam S, Monachello D, Boxem M, Harbort CJ, McDonald N, Gai L, Chen H, He Y; European Union Effectoromics Consortium, Vandenhaute J, Roth FP, Hill DE, Ecker JR, Vidal M, Beynon J, Braun P, Dangl JL. Independently evolved virulence effectors converge onto hubs in a plant immune system network. Science. 2011 Jul 29;333(6042):596-601.

2009

Dreze M, Charloteaux B, Milstein S, Vidalain PO, Yildirim MA, Zhong Q, Svrzikapa N, Romero V, Laloux G, Brasseur R, Vandenhaute J, Boxem M, Cusick ME, Hill DE, Vidal M. 'Edgetic' perturbation of a C. elegans BCL2 ortholog. Nat. Methods. 2009 Nov;6(11):843-9.

Sillé FC, Boxem M, Sprengers D, Veerapen N, Besra G, Boes M. Distinct requirements for CD1d intracellular transport for development of Vα14 iNKT cells. J. Immunol. 2009 Aug 1;183(3):1780-8.

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.

Simonis N, Rual JF, Carvunis AR, Tasan M, Lemmens I, Hirozane-Kishikawa T, Hao T, Sahalie JM, Venkatesan K, Gebreab F, Cevik S, Klitgord N, Fan C, Braun P, Li N, Ayivi-Guedehoussou N, Dann E, Bertin N, Szeto D, Dricot A, Yildirim MA, Lin C, de Smet AS, Kao HL, Simon C, Smolyar A, Ahn JS, Tewari M, Boxem M, Milstein S, Yu H, Dreze M, Vandenhaute J, Gunsalus KC, Cusick ME, Hill DE, Tavernier J, Roth FP, Vidal M. Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network. Nat. Methods. 2009 Jan;6(1):47-54.

2008

Komatsu H, Chao MY, Larkins-Ford J, Corkins ME, Somers GA, Tucey T, Dionne HM, White JQ, Wani K, Boxem M, Hart AC. OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development. PLoS Biol. 2008 Aug 12;6(8):e196.

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.

2006

Boxem M. Cyclin-dependent kinases in C. elegans. Cell Div. 2006 May 12;1:6.

2005

Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M. Towards a proteome-scale map of the human protein-protein interaction network. Nature. 2005 Oct 20;437(7062):1173-8.

2004

Dupuy D, Li QR, Deplancke B, Boxem M, Hao T, Lamesch P, Sequerra R, Bosak S, Doucette-Stamm L, Hope IA, Hill DE, Walhout AJ, Vidal M. A first version of the Caenorhabditis elegans Promoterome. Genome Res. 2004 Oct;14(10B):2169-75.

Boxem M, Tsai CW, Zhang Y, Saito RM, Liu JO. The C. elegans methionine aminopeptidase 2 analog map-2 is required for germ cell proliferation. FEBS Lett. 2004 Oct 8;576(1-2):245-50.

*Vidalain PO, *Boxem M, Ge H, Li S, Vidal M. Increasing specificity in high-throughput yeast two-hybrid experiments. Methods. 2004 Apr;32(4):363-70.
*These authors contributed equally

Tewari M, Hu PJ, Ahn JS, Ayivi-Guedehoussou N, Vidalain PO, Li S, Milstein S, Armstrong CM, Boxem M, Butler MD, Busiguina S, Rual JF, Ibarrola N, Chaklos ST, Bertin N, Vaglio P, Edgley ML, King KV, Albert PS, Vandenhaute J, Pandey A, Riddle DL, Ruvkun G, Vidal M. Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-beta signaling network. Mol. Cell. 2004 Feb 27;13(4):469-82.

*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