Our aim is to understand the role of Rho GTPases and Rho GTPase effectors in vivo during development and disease
Rho GTPases are a family of 22 small GTPases which regulate the organization of the cytoskeleton, but also cell polarity, proliferation, apoptosis, cell-cell contacts and adhesion to the extracellular matrix. Although many studies have characterized the function of Rho GTPases and their effectors in vitro, their in vivo function and particularly their function in disease is less clear.
Mice as models
We therefore generate mice with conditional or constitutive mutations in Rho GTPase genes by targeted mutagenesis. Such mice are excellent models to study the in vivo function of Rho GTPases in specific tissues during development and adulthood. Furthermore, they allow to apply relevant models for diseases such as tumor formation, which are influenced many different parameters such as surrounding extracellular matrix, the neighbouring cells and the immune system.
We furthermore generate mice that allow more specific cell type restricted gene mutations and novel reporter mice in which we can non-invasively track defined cell population or isolate them using fluorescent marker proteins.
Focusing on keratinocytes we try to understand the role of Rho GTPases during skin development, wound healing, skin inflammation and skin cancer and to unravel the underlying molecular mechanisms. We investigate mutant mice by histological examination of skin and analysis of signaling pathways in skin lysates and primary keratinocytes.
Activated fibroblasts producing large amounts of extracellular matrix are the reason for fibrosis, which occurs in many diseases such as diabetes, heart infarction, liver cirrhosis, and scleroderma. Also in cancer so called cancer associated fibroblasts (CAFs) are considered to contribute to disease, by promoting malignant tumor progression and therapy resistance. We suspect that Rho GTPases are important for fibroblast activation and also for the maintenance of their pathological activation and are testing this now using in vitro and in vivo models.
RhoA, Rac1 and Cdc42 differentially regulate aSMA and collagen I expression in mesenchymal stem cells. Ge, J, Burnier, L, Adamopoulou, M, Schaks, M, Rottner, K, Brakebusch, C (2018) . J. Biol Chem., in press
Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation. Li H, Yao Q, Garcia Mariscal A, Wu X, Hülse J, Pedersen E, Helin K, Waisman A, Vinkel C, Thomsen SF, Avgustinova A, Aznar Benitah S, Lovato P, Norsgaard H, Mortensen MS, Veng L, Rozell B, Brakebusch C (2018) . Nat. Comm., in press
Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. García-Mariscal A, Li H, PedersenE, PeyrollierK, Ryan KM, Stanley A, Quondamatteo F, Brakebusch C (2018) Oncogene, 37: 847-860
RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism. García-Mariscal, A., Peyrollier, K.,, Basse A., Pedersen, E., Rühl, R., van Hengel, J., Brakebusch, C. (2016) . Small GTPases. 18:1-12
Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42. Pleines I, Dütting S, Cherpokova D, Eckly A, Meyer I, Morowski M, Krohne G, Schulze H, Gachet C, Debili N, Brakebusch C, Nieswandt B. (2013). Blood. 122: 3178-87
Rac1 regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1. Pedersen E, Wang Z, Stanley A, Peyrollier K, Rösner LM, Werfel T, Quondamatteo F, Brakebusch C. (2012). J. Cell Sci., 125: 5379-5390.
Rho GTPase knockout induction in primary keratinocytes from adult mice. Pedersen E, Basse A, Lefever T, Peyrollier K, Brakebusch C. (2012). Methods Mol. Biol. 827:157-166.
A new mouse model with ‘double-cortex’ reveals cell type specific roles of RhoA in neuronal migration. Cappello S, Böhringer CRJ, Bergami M, Conzelmann K, Srubek Tomassy G, Arlotta P, Mainardi M, Allegra M, Caleo M, van Hengel J, Brakebusch C, Götz M. (2012). Neuron73: 911-24.
RhoA is dispensable for skin development, but crucial for contraction and directed migration of keratinocytes. Jackson B, Peyrollier K, Pedersen E, Basse A, Karlsson R, Wang Z, Lefever T, Ochsenbein A, Schmidt G, Aktories K, Stanley A, Quondamatteo F, Ladwein M, Rottner K, van Hengel J, Brakebusch C. (2011). Mol. Biol. Cell, 22: 593-605.
Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo. Wang Z, Pedersen E, Basse A, Lefever T, Peyrollier K, Kapoor S, Mei Q, Karlsson R, Chrostek-Grashoff A, Brakebusch C. (2010). Oncogene, 29: 3362-3373.
Members of Brakebusch group
Bachelor and Master students
We are always looking for highly motivated Bachelor and Master Students, who want to work on Rho GTPase function in vivo.
PhD and Post Docs
If there is no open call, excellent PhDs and postdoc interested in Rho GTPase function can apply with a project from our group for fellowships and stipends at different foundations throughout the year. These projects could involve for example Rho GTPase function in diseases, but also their role in development or in cellular functions such as migration, regulation of gene expression, or T cell receptor signaling. Also suggestions for new projects are welcome!
Please contact firstname.lastname@example.org for current opportunities.
Cover photo - Journal of Cell Science