Evaluation of cytoskeleton dynamics in neuronal development in MAP6 knockout mice

BISBAL M., PERIS L., POUZET B., WETTSTEIN J., ANDRIEUX A.

New Jersey

Simposio; 2nd Roche Symposium of the Postdoctoral Fellowship Program; 2011

F. Hoffmann-La Roche Ltd

Alterations of microtubule dynamics have been involved in several neurodegenerative pathologies and in some cases the alterations have been proposed to be causal e.g. the abnormal modifications of the microtubule associated protein Tau in Alzheimer disease. Our laboratory has provided one of the first experimental evidence for a role of microtubules in mental functions by developing a mouse model deficient for a microtubule associated proteins known as STOPs.   STOP-deficient mice exhibited severe alterations of brain functions with neurotransmission anomalies and sensorimotor gating impairment, associated with severe behavioral deficits that react positively to antipsychotic drugs after chronic treatments. The STOP-null mice also show global reduction of the brain mass, associated with widespread deficits in axonal extensions, whereas the number of neurons seems unaffected, an observation similar to post-mortem observation in patients with schizophrenia. However little is known about the biological fuction and the cellular targets of STOP protein in neurons. Bering in mind all these considerations, the aim and the proposal of this project is to evaluate microtubules and actin dynamics during axonal differentiation and dendritic spine formation in STOP-deficient neurons and to analyze the role of STOPs proteins in synaptic plasticity, all events that are defective in neuronal pathologies. Here we show that the different isoforms of STOP are developmentally regulated. At early stages E-STOP specifically localized to the axon where stabilize microtubules. Using STOP knockdown neurons and overexpresion experiments we show that STOP proteins are important for axonal polarization and regulate neuronal diferentiation. Finally we also observed that STOP knockdown neuron have less dendritic spines, and the overexpresion of the N-STOP isoform rescues dendritic spines number, suggesting a role of STOP proteins in spinogenesis. Thus, our data reveal that STOP proteins are important to regulate neuronal differentiation and maturation. Altogether this project will provide a better understanding of how microtubules dynamic is involved in neuronal plasticity, propose potential molecular targets involved in the modulation of cytoskeletal dynamic parameters and allow us understanding the precise role of microtubule and actin cytoskeleton in neuronal and psychiatric disease. Finding targets that modulate cytoskeletal dynamics might provide successful treatment of pathologies where synaptic connectivity is dysfunctional, like schizophrenia.