Developmental Biology

a worm

Dr. Mike Boxem

Research summary

My group uses a combination of systems biology approaches, systematic experimental manipulation, and live-cell imaging to study the process of cell polarization. Cell polarity – the asymmetric distribution of components or functions within a cell – is a basic property of most cells that is essential in development and for the functioning of adult tissues. For example, polarity is required for the generation of different cell types through asymmetric cell divisions, and most cell types need to establish functionally distinct domains to perform their functions. Cell polarity is mediated by mutually inhibitory interactions between several groups of cortical proteins.

The most abundant polarized cell type of the animal body is the epithelial cell. Polarization of epithelial cells into apical and basolateral domains is essential for epithelia to be able to function as selectively permeable barriers. Loss of epithelial polarity contributes to epithelial diseases like polycystic kidney disease and retinal dystrophies. Moreover, epithelial cancers are characterized by loss of cell polarity and epithelial integrity, and many polarity regulators are mutated or deregulated in cancer.

Research in our group addresses three main polarity-related questions:

  1. What are the functional interactions that maintain polarity in existing epithelial tissues?
  2. What are the direct consequences of loss of polarity to the behavior and fate of cells, and how does loss of polarity predispose cells to overproliferation?
  3. How is cortical polarity connected with other cellular processes that contribute to cell polarity?

polarity examples

To address these questions, we make use of Caenorhabditis elegans as a model system. This small nematode has multiple epithelial tissues, and the proteins that control polarity are conserved between C. elegans and human. C. elegans is ideal for live observations of cell polarity due to its transparency and small number of cells. In combination with recent technological advances made possible by the use of CRISPR-based genome engineering, we can now precisely manipulate polarity in living tissues, and follow the effects on epithelial tissues and on the polarizing machinery with unprecedented detail and accuracy. Moreover, using genetic screens we can identify components that act in concert with cortical polarity regulators to establish the full polarized cell morphology.

People

Current lab members:

Former lab members:

  • Thijs Koorman (Ph.D student)
  • Monique van der Voet (Postdoc)
  • Selma Waaijers (Ph.D student)

Publications

2017

Amendola PG, Zaghet N, Ramalho JJ, Vilstrup Johansen J, Boxem M, Salcini AE. JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity. PLoS Genet. 2017 Feb 16;13(2).

2016

Portegijs V, Fielmich LE, Galli M, Schmidt R, Muñoz J, van Mourik T, Akhmanova A, Heck AJ, Boxem M, van den Heuvel S. Multisite phosphorylation of NuMA-related LIN-5 controls mitotic spindle positioning in C. elegans. PLoS Genet. 2016 Oct 6;12(10).

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.

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.

Chen L, Chuang M, Koorman T, Boxem M, Jin Y, Chisholm AD. Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase. Elife. 2015 Sep 4;4.

2015

Waaijers S, Ramalho JJ, Koorman T, Kruse E, Boxem M. The C. elegans Crumbs family contains a CRB3 homolog and is not essential for viability. Biol. Open. 2015 Feb 6.

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.

2014

Sapir A, Tsur A, Koorman T, Ching K, Mishra P, Bardenheier A, Podolsky L, Bening-Abu-Shach U, Boxem M, Chou TF, Broday L, Sternberg PW. Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging. Proc. Natl. Acad. Sci. U.S.A.. 2014 Sep 16;111(37):E3880-9.

de Albuquerque BF, Luteijn MJ, Cordeiro Rodrigues RJ, van Bergeijk P, Waaijers S, Kaaij LJ, Klein H, Boxem M, Ketting RF. PID-1 is a novel factor that operates during 21U-RNA biogenesis in Caenorhabditis elegans. Genes Dev. 2014 Apr 1;28(7):683-8.

Waaijers S, Boxem M. Engineering the Caenorhabditis elegans genome with CRISPR/Cas9. Methods. 2014 Mar 28.

2013

Wang Z, Hou Y, Guo X, van der Voet M, Boxem M, Dixon JE, Chisholm AD, Jin Y. The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons. Neuron. 2013 Sep 4;79(5):903-16.

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.

*Waaijers S, *Koorman T, Kerver J, Boxem M. Identification of human protein interaction domains using an ORFeome-based yeast two-hybrid fragment library. J. Proteome Res. 2013 Jul 5;12(7):3181-92.
*These authors contributed equally

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.

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 Nov;7(11)

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