By exploiting systemic and conditional knockout mouse models for actin-binding proteins, we aim to understand the regulation of neuronal actin dynamics and its relevance for mammalian brain development and functionality.
Currently, our research focuses on three topics:
- Relevance of ADF/cofilin for synaptic function and behavior
In excitatory synapses, actin filaments determine the morphology of postsynaptic compartments, termed dendritic spines, and activity-driven reorganization of the postsynaptic actin cytoskeleton is thought to be relevant for synaptic plasticity (long-lasting changes in synaptic transmission), learning, and memory. Moreover, actin has been implicated in the mobilization and exocytosis of synaptic vesicles. Although the relevance of actin dynamics for pre- and postsynaptic mechanisms is well established, knowledge about upstream regulatory mechanisms is rather limited. By exploiting gene-targeted mice, we found a crucial role of cofilin-1 (n-cofilin), a member of the ADF/cofilin family of actin depolymerizing proteins, in synaptic plasticity and learning. Conversely, ADF, another ADF/cofilin family member that is broadly expressed in the brain and present at excitatory synapses, is dispensable for synapse physiology, and ADF mutant mice did not show any obvious behavioral defects. Since our data suggest compensatory mechanisms in single mutant mice and overlapping synaptic functions of ADF and cofilin-1, we currently study double mutant mice to comprehensively characterize the synaptic function of ADF/cofilin proteins. For more information, please see: Wolf et al., 2014; Zimmermann et al., 2014; Goodson et al., 2012; Görlich et al., 2011; Rust et al., 2010; Herde et al., 2010.
- Functional role of profilin1 in mammalian brain development
Profilins can bind monomeric actin and are thought to be relevant for actin dynamics. Genetic studies in non-vertebrate model systems suggest a role for profilins in nervous system development. Two profilin family members are present in the mammalian central nervous system (CNS), namely profilin1 and profilin2. Analysis of mutant mice revealed that profilin2 is dispensable for CNS development, but that it has acquired a specific function in synaptic vesicle exocytosis. Conversely, we found that profilin1 inactivation in mice does not affect synaptic function, but impairs brain development. Specifically, profilin1 is required for glia cell binding and radial migration of cerebellar granule neurons (CGN). By exploiting conditional profilin1 mutants and transgenic mice expressing Cre recombinase in various cell types, we aim to unravel the profilin1-dependent mechanism in radial CGN migration. For more information, please see: Kullmann et al., 2012a; Rust et al, 2012; Kullmann et al., 2012b; Görlich et al., 2012.
- Mitochondrial function of ADF/cofilin
We and others found that, under certain experimental conditions, ADF/cofilin proteins can interact with mitochondria in mammalian cells. However, their relevance for mitochondrial function remains elusive. By using mouse embryonic fibroblasts as a model system, we study the role of ADF/cofilin in apoptosis signaling and in mitochondrial dynamics. For more information, please see: Rehklau et al., 2012.
- Dr. Rust, Marco (Head of the Group)
- Burk, Karlheinz (Technical Assistance)
- Damar, Fidan (Msc Student)
- Meyer, Sophie (PhD Student)
- Möller, Janika (PhD Student)
- Kepser, Lara-Jane (PhD Student)
- Schneider, Felix (MSc Student)
Former lab members
- Dr. Görlich, Andreas (now Postdoc in the lab of Nathaniel Heintz at the Rockefeller University in New York, USA)
- Dr. Kullmann, Jan (now Postdoc in the lab of David Solecki at the St. Jude Children’s Research Hospital in Memphis, USA)
- Dr. Rehklau, Katharina (now Postdoc in the lab of Nathaniel Heintz at the Rockefeller University in New York, USA)
- Wolf, Michael (now Clinical Data Coordinator at CRI in Munich, Germany)
- Dr. Zimmermann, Anika-Maria (now Editor at Thieme Medical Publishers in Stuttgart, Germany)
- Strecker P, Ludewig S, Rust MB, Mundinger TA, Görlich A, Krächan EG, Mehrfeld C, Herz J, Korte M, Guénette SY, Kins S. FE65 and FE65L1 share common synaptic functions and genetically interact with the APP family in neuromuscular junction formation. Sci Rep 6:25652
- Rust MB & Michaelsen-Preusse K. (2016). Form follows function: actin-binding proteins as critical regulators of excitatory synapses. e-Neuroforum, 7(1):7-12.
- van der Kooij MA, Masana M, Rust MB, Müller MB. (2016) The stressed cytoskeleton: How actin dynamics can shape stress-related consequences on synaptic plasticity and complex behavior. Neurosci Biobehav Rev, 62:69-75.
- Rust MB (2015). Novel functions for ADF/cofilin in excitatory synapses – lessons from gene-targeted mice. Commun Integr Biol, 8(6):e1114194-3.
- Rust MB (2015). ADF/cofilin: a crucial regulator of synapse physiology and behavior. Cell Mol Life Sci, 72(18): 3521-3529.
- Rust MB & Maritzen T (2015). Relevance of presynaptic actin dynamics for synapse function and mouse behavior. Exp Cell Res, 335(2):165-171.
- Kullmann JA, Wickertsheim I, Minnerup L, Costell M, Friauf E, Rust MB (2015). Profilin1 activity in cerebellar granule neurons is required for radial migration in vivo. Cell Adh Migr, (3):247-253.
- Zimmermann AM, Jene T, Wolf M, Görlich A, Gurniak CB, Sassoè-Pognetto M, Witke W, Friauf E, Rust MB (2015). ADHD-like phenotype in a mouse model with impaired synaptic actin dynamics. Biol Psychiatry, 78(2): 95-106.
- Wolf M, Zimmermann AM, Görlich A, Gurniak CB, Sassoè-Pognetto M, Friauf E, Witke W, Rust MB (2015). ADF/cofilin controls synaptic actin dynamics and regulates synaptic vesicle mobilization and exocytosis. Cereb Cortex, 25(9): 2863-2875
- Önel SF, Rust MB, Jacob R, Renkawitz-Pohl R. (2014). Tethering membrane fusion: Common and different players in myoblasts and at the synapse. J Neurogenet, 28(3-4): 302-15
- Pirone A, Kurt S, Zuccotti A, Rüttiger L, Pilz P, Brown D, Franz C, Schweizer M, Rust MB, Rübsamen R, Friauf E, Knipper M, Engel J (2014). α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders. J Neurosci, 34(2): 434-445.
- Shmukler BE, Hsu A, Alves J, Trudel M, Rust MB, Hubner CA, Rivera A, Alper SL (2013). N-ethylmaleimide activates a Cl-independent component of K flux in mouse erythrocytes. Blood Cells Mol Dis 51(1): 9-16.
- Goodson M, Rust MB, Witke W, Bannerman D, Mott R, Ponting CP, Flint J (2012). Cofilin-1: a modulator of anxiety in mice. PLoS Genetics 8(10): e1002970.
- Kullmann JA, Neumeyer A, Wickertsheim I, Deitmer JW, Witke W, Friauf E, Rust MB (2012). Purkinje cell loss and motor coordination defects in profilin1 mutant mice. Neuroscience 223:355-364.
- Rehklau K, Gurniak CB, Conrad M, Friauf E, Ott M, Rust MB (2012). ADF/cofilin proteins translocate to mitochondria during apoptosis but are not generally required for cell death signaling. Cell Death Differ 19(6): 958-967.
- Rust MB, Kullmann JA, Witke W (2012). Role of the actin-binding protein profilin1 in radial migration and glial cell adhesion of granule neurons in the cerebellum. Cell Adh Migr 6(1): 1-5.
- Görlich A, Zimmermann AM, Schober D, Böttcher RT, Sassoé-Pognetto M, Friauf E, Witke W, Rust MB (2012). Preserved morphology and physiology of excitatory synapses in profilin1 deficient mice. PLoS ONE 7(1): e30068.
- Kullmann J, Neumeyer A, Gurniak CB, Friauf E, Witke W, Rust MB (2012). Profilin1 activity in cerebellar granule neurons is required for glial cell contact and radial migration. EMBO Rep 13(1): 75-82.
- Görlich A, Wolf M, Zimmermann AM, Gurniak, CB, Al Banchaabouchi M, Sassoé-Pognetto M, Witke W, Friauf E, Rust MB (2011). N-cofilin can compensate for the loss of ADF in excitatory synapses. PLoS ONE 6(10): e26789.
- Friauf E, Rust MB, Schulenborg T, Hirtz J (2011). Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system. Hear Res 279(1-2): 96-110
- Rust MB, Gurniak CB, Renner M, Vara H, Giustetto M, Morando L, Görlich A, Sassoè-Pognetto M, Al Banchaabouchi M, Triller A, Choquet D, Witke W (2010). Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. EMBO J 29(11): 1889-1902.
- Herde MK, Friauf E, Rust MB (2010). Developmental expression of the actin depolymerizing factor ADF in the mouse inner ear and spiral ganglia. J Comp Neurol 518(10): 1724-1741.
- Rust MB, Alper SL, Rudhard Y, Shmukler BE, Vicente R, Brugnara C, Trudel M, Jentsch TJ, Hubner CA (2007). Disruption of erythroid KCl-cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest 117(6): 1708-1717.
- Hubner CA and Rust MB (2007). Physiology of Cation-Chloride Co-transporters in Chloride Movements across Cellular Membranes. Advances in Molecular and Cell Biology, Vol 38, 241-77 (Elsevier/Academic Press)
- Rust MB, Faulhaber J, Budack M, Pfeffer C, Maritzen T, Didié M, Beck FX, Boettger T, Schubert R, Ehmke H, Jentsch TJ, Hubner CA (2006). Neurogenic mechanisms contribute to hypertension in mice with disruption of the K-Cl cotransporter KCC3. Circ Res 98(4): 549-556.
- Huber SM, Duranton C, Henke G, Shumilina E, Sandu CD, Tanneur V, van de Sand C, Heussler V, Brand V, Kasinathan RS, Lang KS, Kremsner PG, Hubner CA, Rust MB, Dedek K, Jentsch TJ, Lang F (2004). Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte. J Biol Chem 279(40): 41444-52
- Boettger T, Rust MB, Maier H, Seidenbecher T, Schweizer M, Keating DJ, Faulhaber J, Ehmke H, Pfeffer C, Scheel O, Lemcke B, Horst J, Leuwer R, Pape HC, Volkl H, Hubner CA, Jentsch TJ (2003). Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 22(20): 5422-34
- Boettger T, Hubner CA, Maier H, Rust MB, Beck FX, Jentsch TJ (2002). Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature 416(6883): 874-878