Analysis of n-cofilin mediated actin dynamics in cortical neuron migration and the link to lissencephaly-like disorders

• Applicant: Professor Dr. Walter Witke
• Subject Area: Developmental Neurobiology
• Term: from 2009 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 106863844

Migration of neuronal precursor cells is a key feature of brain morphogenesis and failure of neurons to reach their destination results in severe neurological disorders including autism, epilepsy, schizophrenia and mental retardation. The cortex as the largest brain region is a seven-layered structure that is built in an outside-in fashion and particularly dependent on neuronal migration. Neurons born in the ventricular zone have to cross the existing inner layers in order to setup the new outer layers. Disruption of this process leads to Lissencephaly, a syndrome that comprises various degrees of anatomical defects due to impaired neuronal migration. The mechanisms, which govern cortical neuron migration are only partly understood. We know that one important pathway is microtubule dependent and controlled by a protein network including LIS1 (Lissencephaly locus), Nde1 (NudE-like) and other MAPs. At this juncture, little is known about the role of actin filament dynamics in cortical migration and the etiology of neuronal migration disorders. Using conditional mouse models for the F-actin depolymerizing protein n-cofilin, we could show that in mammals radial migration as well as the cell cycle of neuronal precursors are controlled by the actin cytoskeleton. In mouse, mutation of the n-cofilin gene results in a lissencephaly-like phenotype. The proposal builds on these findings and aims to characterize the cellular and molecular mechanisms by which n-cofilin dependent actin dynamics contribute to neuronal migration and development of the cortex. We will take an interdisciplinary approach, making use of conditional mouse mutants, primary cell lines and biochemistry to study neuronal migration in the cortex. We anticipate that this project will provide insights into the general mechanisms which rule neuronal migration, and it will highlight novel aspects of actin in cortical development and associated human diseases.

• DFG Programme: Research Grants