85 billion neurons present in adult human brain form over 1014 connections (synapses) with unprecedented precision essential for normal function of the nervous system. Large number of the connections is established during embryonic development indicating that the intrinsic molecular mechanisms guiding the growing axons/dendrites play the key role in their formation. In order to reach their destination the growing neurites recognize gradients of extracellular cues, which are translated by intracellular signaling cascades into changes of microtubule dynamics, which determine the exact extent of neurite growth vs. collapse. The molecular mechanisms responsible for the precise translation of the extracellular gradients are so far largely unknown.
We have found that conformational changes of phosphorylated microtubule associated proteins catalyzed by peptidyl prolyl cis-trans isomerase Pin1 specifically regulate axon guidance and that defects in this regulatory pathway result in aberrant axon growth. Using in vitro neuron cultures and in vivo mouse models we characterize the role of conformational regulation in the axon/dendrite growth and arborization, in the onset of neurodevelopmental disorders and in the axon regeneration upon central nervous system injury.