Dr. A.J. (Jeffrey) van Haren

Jeffrey van Haren received his PhD in 2009 from the Erasmus MC, where he studied the regulation of the mammalian microtubule cytoskeleton, and functionally characterized factors that regulate neuronal outgrowth. He then did a postdoctoral training at the UCSF (San Francisco) from 2012-2019, where he focused on the development and implementation of novel optogenetics tools that enable the use of light patterns to control the activity of proteins with unprecedented spatio-temporal  resolution. He has recently returned to the Erasmus MC to start his own research group, where he aims to study the molecular basis of directional neuronal cell migration, by combining optogenetic tool development, micropatterning and quantitative live cell microscopy.

Group members:
Jeffrey van Haren, PhD
Tim Allertz, PhD student
Cristina Márquez González, BSc student

Contact information:
Name: Jeffrey van Haren
Telephone:  +31-1070 43164
E-mail: a.vanharen@erasmusmc.nl

Visiting address:
Dept. of Cell Biology
Erasmus MC
Faculty building
Room Ee-1002c
Wytemaweg 80
3015 CN Rotterdam
The Netherlands

Postal address:
Dept. of Cell Biology
Erasmus MC
Faculty building
Room Ee-1002c
PO Box 2040
3000 CA Rotterdam
The Netherlands

Understanding and controlling cellular guidance mechanisms

The main goals of our group are: 1) to understand the molecular machinery that enables cells to move in a directional and coherent manner, and  2) to control this machinery to instruct cells to move in a defined and precisely controllable manner in order to reconstitute and study complex cell/tissue architectures. 

Directed cell migration is of critical importance during embryonic development, wound repair, and immune responses. Our lab is particularly interested in the molecules that control directional outgrowth of neuronal cells that during development of the nervous system must find their targets over very long distances. Knowing where to go requires sensing the environment and picking up on subtle gradients of various guidance cues, which in the case of neurons includes chemotactants (such as netrins) secreted by cells at a distance. How do cells accomplish this? How does local detection of guidance molecules lead to large scale reorganization of the cell? We aim to understand the molecular machinery inside cells that interprets and integrates guidance signals and that directs an appropriate cellular response.

A structure at the tip of neuronal extensions, termed the growth cone, is responsible for neuronal pathfinding, and is able to autonomously navigate towards or away from guidance cues. How growth cones do this is not well understood, e.g. we don’t know all the molecules involved,  how cytoskeletal systems are coordinated and how feedback mechanisms ensure that one side of the growth cones continues to protrude upstream (or downstream) of a gradient, while the other side retracts (and follows). Most importantly, we don’t understand how signals are processed in space and time. Our lack in understanding in part comes from our inability to locally control proteins. 

To pinpoint how, when and where a certain protein is important one needs precise spatiotemporal control of the protein in question. To accomplish this we develop and utilize novel optogenetics tools that allow us to locally control the activity of proteins with high spatial resolution. This allows us to develop novel strategies to precisely manipulate cell external cues,  and cell intrinsic mechanism in space and time. We combine optogenetic tool development with advanced live cell microscopy and micropatterning to observe and control the components of the cell guidance machinery. We also utilize state of the art molecular biology tools including CRISPR to KO genes or tag proteins for visualization, and protein interaction screens/ mass spectrometry to identify the molecular components of cell guidance mechanisms. For our studies we employ iPSc derived neurons, that are amenable to genetic engineering and allow for insertion of genetically encoded optical control modules.

We work at the interface between cell and syntheticbiology, and we build novel  precisely controllable molecular switches and levers to gain a better understanding of fundamental biological mechanisms. Knowledge generated from our studies will contribute to a better understanding of neurodevelopmental disorders, will enable novel tissue engineering/regeneration strategies, and might form the basis for novel tissue-computer interfaces.

Dema A, van Haren J, Wittmann T. Optogenetic EB1 inactivation shortens metaphase spindles by disrupting cortical force-producing interactions with astral microtubules. Current Biology, 2022 Mar 14;32(5):1197-1205.e4. doi: 10.1016/j.cub.2022.01.017. Epub 2022 Jan 31. PMID: 35090591; PMCID: PMC8930524. https://www.cell.com/current-biology/fulltext/S0960-9822(22)00028-8

Stormo AED, Shavarebi F, FitzGibbon M, Earley EM, Ahrendt H, Lum LS, Verschueren E, Swaney DL, Skibinski G, Ravisankar A, van Haren J, Davis EJ, Johnson JR, Von Dollen J, Balen C, Porath J, Crosio C, Mirescu C, Iaccarino C, Dauer WT, Nichols RJ, Wittmann T, Cox TC, Finkbeiner S, Krogan NJ, Oakes SA, Hiniker A. The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity. Journal of Cell Biology, 2022 Apr 4;221(4):e202010065. doi: 10.1083/jcb.202010065. Epub 2022 Mar 10. PMID: 35266954; PMCID: PMC8919618. https://rupress.org/jcb/article/221/4/e202010065/213061/The-E3-ligase-TRIM1-ubiquitinates-LRRK2-and

Dema A, Rahgozar S, Siquier L, van Haren J, Wittmann T. Controlling Cell Shape and Microtubule Organization by Extracellular Matrix Micropatterning. Methods Mol Biol. 2022;2430:467-481. doi: 10.1007/978-1-0716-1983-4_29. PMID: 35476350. https://pubmed.ncbi.nlm.nih.gov/35476350/

Sánchez-Huertas C, Bonhomme M, Falco A, Fagotto-Kaufmann C, van Haren J, Jeanneteau F, Galjart N, Debant A, Boudeau J. The +TIP Navigator-1 is an actin-microtubule crosslinker that regulates axonal growth cone motility. Journal of Cell Biology. 2020 Sep 7;219(9):e201905199. doi: 10.1083/jcb.201905199. PMID: 32497170; PMCID: PMC7480110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480110/

Wittmann T*, Dema A, van Haren J*. Lights, cytoskeleton, action: Optogenetic control of cell dynamics. Current Opinion in Cell Biology. 2020; doi: 10.1016/j.ceb.2020.03.003, *Corresponding Author. https://www.sciencedirect.com/science/article/pii/S0955067420300454?dgcid=coauthor

van Haren J, Adachi LS, Wittmann T. Optogenetic Control of Microtubule Dynamics. Methods Mol Biol. 2020;2101:211-234. doi: 10.1007/978-1-0716-0219-5_14. PubMed PMID: 31879907. https://link.springer.com/protocol/10.1007%2F978-1-0716-0219-5_14

van Haren J*, Wittmann T*. Microtubule Plus End Dynamics - Do We Know How Microtubules Grow?: Cells boost microtubule growth by promoting distinct structural transitions at growing microtubule ends. Bioessays. 2019 Mar;41(3):e1800194. doi: 10.1002/bies.201800194. Epub 2019 Feb 7. PubMed PMID: 30730055. *Corresponding Author.
https://onlinelibrary.wiley.com/doi/full/10.1002/bies.201800194

van Haren J, Charafeddine RA, Ettinger A, Wang H, Hahn KM, Wittmann T. Local control of intracellular microtubule dynamics by EB1 photodissociation. Nature Cell Biology, 2018 Mar 20; (3):252-261. doi: 10.1038/s41556-017-0028-5. Epub 2018 Jan 29.
https://www.nature.com/articles/s41556-017-0028-5

Wittmann T, van Haren J. Generation of cell lines with light-controlled microtubule dynamics. Protocol Exchange, 2018, published online 29 January 2018. doi:10.1038/protex.2017.155 https://protocolexchange.researchsquare.com/article/nprot-6427/v1

Pemble H, Kumar P, van Haren J, Wittmann T. GSK3-mediated CLASP2 phosphorylation modulates kinetochore dynamics. Journal of Cell Science, 2017 Apr 15; 130(8):1404-1412. doi: 10.1242/jcs.194662. Epub 2017 Feb 23. 
https://jcs.biologists.org/content/130/8/1404.abstract

Ettinger A, van Haren J, Ribeiro SA, Wittmann T. Doublecortin Is Excluded from Growing Microtubule Ends and Recognizes the GDP-Microtubule Lattice. Current Biology, 2016 Jun 20; 26(12):1549-1555. doi: 10.1016/j.cub.2016.04.020. Epub 2016 May 26.
https://www.sciencedirect.com/science/article/pii/S0960982216303426?via%3Dihub 

van Haren J, Boudeau J, Schmidt S, Basu S, Liu Z, Lammers D, Demmers J, Benhari J, Grosveld F, Debant A, Galjart N. Dynamic microtubules catalyze formation of navigator-TRIO complexes to regulate neurite extension. Current Biology, 2014 Aug 4; 24(15):1778-85. doi: 10.1016/j.cub.2014.06.037. Epub 2014 Jul 24.
https://www.cell.com/article/S0960-9822(14)00753-2/fulltext

Ruiz-Saenz A, van Haren J, Sayas CL, Rangel L, Demmers J, Millán J, Alonso MA, Galjart N, Correas I. Protein 4.1R binds to CLASP2 and regulates dynamics, organization and attachment of microtubules to the cell cortex. Journal of Cell Science, 2013 Oct 15; 126(Pt 20):4589-601. doi: 10.1242/jcs.120840. Epub 2013 Aug 13. 
https://jcs.biologists.org/content/126/20/4589

Ghamari A, van de Corput MP, Thongjuea S, van Cappellen WA, van Ijcken W, van Haren J, Soler E, Eick D, Lenhard B, Grosveld FG. In vivo live imaging of RNA polymerase II transcription factories in primary cells. Genes and Development, 2013 Apr 1; 27(7):767-77. doi: 10.1101/gad.216200.113. 
https://www.ncbi.nlm.nih.gov/pubmed/23592796

Drabek K, Gutiérrez L, Vermeij M, Clapes T, Patel SR, Boisset JC, van Haren J, Pereira AL, Liu Z, Akinci U, Nikolic T, van Ijcken W, van den Hout M, Meinders M, Melo C, Sambade C, Drabek D, Hendriks RW, Philipsen S, Mommaas M, Grosveld F, Maiato H, Italiano JE Jr, Robin C, Galjart N. The microtubule plus-end tracking protein CLASP2 is required for hematopoiesis and hematopoietic stem cell maintenance. Cell Reports. 2012 Oct 25; 2(4): 781-8. doi: 10.1016/j.celrep.2012.08.040. Epub 2012 Oct 19. 
https://www.sciencedirect.com/science/article/pii/S2211124712002811

Schmidt N, Basu S, Sladecek S, Gatti S, van Haren J, Treves S, Pielage J, Galjart N, Brenner HR. Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane. Journal of Cell Biology. 2012 Aug 6; 198(3): 421-37. doi: 10.1083/jcb.201111130. Epub 2012 Jul 30.
https://rupress.org/jcb/article/198/3/421/53551/Agrin-regulates-CLASP2-mediated-capture-of

Lee HS, Komarova YA, Nadezhdina ES, Anjum R, Peloquin JG, Schober JM, Danciu O, van Haren J, Galjart N, Gygi SP, Akhmanova A, Borisy GG. Phosphorylation controls autoinhibition of cytoplasmic linker protein-170. Molecular Biology of the Cell, 2010 Aug 1; 21(15):2661-73. doi: 10.1091/mbc.E09-12-1036. Epub 2010 Jun 2.
https://www.molbiolcell.org/doi/full/10.1091/mbc.e09-12-1036

Stepanova T, Smal I, van Haren J, Akinci U, Liu Z, Miedema M, Limpens R, van Ham M, van der Reijden M, Poot R, Grosveld F, Mommaas M, Meijering E, Galjart N. History-dependent catastrophes regulate axonal microtubule behavior. Current Biology, 2010 Jun 8; 20(11):1023-8. doi: 10.1016/j.cub.2010.04.024. Epub 2010 May 13.
https://www.cell.com/current-biology/fulltext/S0960-9822(10)00501-4

van Haren J, Draegestein K, Keijzer N, Abrahams JP, Grosveld F, Peeters PJ, Moechars D, Galjart N. Mammalian Navigators are microtubule plus-end tracking proteins that can reorganize the cytoskeleton to induce neurite-like extensions.  Cell Motilily and the Cytoskeleton, 2009 Oct; 66(10):824-38. doi: 10.1002/cm.20370. 
https://onlinelibrary.wiley.com/doi/epdf/10.1002/cm.20370

Dragestein KA, van Cappellen WA, van Haren J, Tsibidis GD, Akhmanova A, Knoch TA, Grosveld F, Galjart N. Dynamic behavior of GFP-CLIP-170 reveals fast protein turnover on microtubule plus ends. Journal of Cell Biology, 2008 Feb 25; 180(4):729-37. doi: 10.1083/jcb.200707203. Epub 2008 Feb 18. https://rupress.org/jcb/article/180/4/729/53727/Dynamic-behavior-of-GFP-CLIP-170-reveals-fast