Analysis of n-cofilin mediated actin dynamics in cortical neuron migration and the link to lissencephaly-like disorders
Final Report Abstract
The main goal of this project was to understand the mechanisms by which the Cofilin/ADF family of proteins regulate cortical development, neuronal migration and synaptic physiology. In all three areas our studies have generated significant advances. We could show that Cofilin1 functions in a cell autonomous fashion, to control neuronal migration independent from other cell types such as glia cells. Our data suggest that Cofilin1/ADF are together the key molecules for controlling actin dynamics and retrograde F-actin flow in the growth cone of neurites. On the molecular level Cofilin1/ADF indirectly regulate microtubule by generating an allocated space for the extension of microtubules into the extending neurite. In cultured cortical neurons we could show that this mechanism leads to a robust persistence during directed migration. Deletion of Cofilin1 leads to an increased turning rate, resulting in an impaired net translocation of neurons. These defects help to explain the aberrant cortical layering, which we observed in mouse mutants for Cofilin1. In Cofilin1/ADF double mutants the cortex as a structure is essentially missing, while other regions of the brain can still develop. These data suggest that Cofilin1/ADF represent the master switch, determining the architecture of the developing cortex in vertebrates. Recent unpublished data from our group even suggest that the evolutionary switch in ray-finned fish to an everted brain structure might have been triggered by point mutations in the Cofilin/ADF genes. In the second part of the project we could decode the synaptic functions of Cofilin1 and ADF. We showed that Cofilin1 is essential for controlling postsynaptic parameters such as receptor mobilization, LTP and LTD. Also, number and size of dendritic spines are controlled by Cofilin1. Mutant mice lacking Cofilin1 in the forebrain show a very specific learning deficit. While exploratory learning and memory is fully functional, mice lacking Cofilin1 are not able to associate learning tasks with reward or aversive stimuli. ADF on the other hand functions together with Cofilin1 in a common pathways on the presynaptic side in regulating vesicle release. Interestingly, both proteins can compensate each other in their presynaptic activity, but not in their postsynaptic function. Lack of both Cofilin1/ADF leads to an increase in presynaptic vesicle release at excitatory synapses and an imbalance of neurotransmitter levels. Forebrain specific mutant mice for Cofilin1/ADF suffer from ‚functional hyperdopaminergia‘ and due to their behavioral alterations provide a valid model for ADHS (Attention Deficit Hyperactivity Syndrome). Blocking dopaminergic receptors, or administering Ritalin (methylphenidate) was shown to rescue the ADHS phenotype and ameliorate the genetic defect in Cofilin1/ADF mutant mice.
Publications
- (2010): Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. EMBO J., 29(11), 1889-902
Rust, M., Gurniak, C., Renner, M., Vara, H., Morando, L., Görlich, A., Sassoe-Pognetto, M., Al Banchaabouchi, M., Giustetto, M., Triller, A., Choquet, D., Witke, W.
- (2012): ADF/cofilin-mediated actin turnover directs neurite formation in the developing brain through its severing activity. Neuron, Dec 20; 76(6): 1091-107
Flynn, K., Neukirchen, D., Jacobs, S., Tahirovic, S., Garvalov, BK., Meyn, L.,Gurniak, CB.,Wedlich-Söldner, R., Small, JV., Witke, W., Bradke, F.
- (2012): Cofilin-1: a modulator of anxiety in mice. PLoS Genetics, 8(10):e1002970
Goodson, M., Rust, MB., Witke, W., Bannerman, D., Mott, R., Ponting, CP., Flint, J.
(See online at https://doi.org/10.1371/journal.pgen.1002970) - (2014): ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis. Cerebral Cortex., Apr 25, Epub ahead of print
Wolf, M., Zimmermann, AM., Görlich, A., Gurniak, CB., Sassoè-Pognetto, M., Friauf, E., Witke, W., Rust, M.
(See online at https://doi.org/10.1093/cercor/bhu081) - (2014): Attention-Deficit/Hyperactivity Disorder-like Phenotype in a Mouse Model with Impaired Actin Dynamics. Biol. Psychiatry, March 21(14), Epub ahead of print
Zimmermann, AM., Jene, T., Wolf, M., Görlich, A., Gurniak, CB., Sassoè-Pognetto, M., Witke, W., Friauf, E., Rust, M.
(See online at https://doi.org/10.1016/j.biopsych.2014.03.011) - (2014): Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance. European Journal of Cell Biology, May-June; 93 (5-6), 252-66
Gurniak, C.B., Chevessier, F., Jokwitz, M., Jönsson, F., Perlas, E., Richter, H., Matern, G., Pilo Boyl, P., Chaponnier, C., Fürst, D., Schröder, R., Witke, W.
(See online at https://doi.org/10.1016/j.ejcb.2014.01.007)
