Intranet Areál web

Lecture "Microtubule associated proteins and their regulation - between brain development and disease"

Brain development relies on the precise regulation of neuron migration, axon/dendrite growth, guidance, synapse formation and refinement. A critical role in the process is played by microtubules and their deregulation, due to changes in microtubule-associated proteins (MAPs), has been associated with pathogenesis of neurodevelopmental disorders as autism spectrum disorder (ASD), epilepsy or schizophrenia. 

We have shown that deficiency in microtubule associated protein CRMP2 results in defective axon guidance, synapse pruning and histological and behavioral changes associated ASD. Furthermore, we found that one isoform of CRMP2 (CRMP2A) significantly increases tubulin polymerization and is largely responsible for the developmental phenotype of CRMP2 KO mice. CRMP2 activity is inhibited by phosphorylation. Previously, we demonstrated that conformational changes of CRMP2A, catalyzed by prolyl isomerase Pin1, counteract the inhibitory effect of phosphorylation, stabilize CRMP2A in the distal axons and promote axon growth. Now, we found that the unphosphorylated CRMP2A is conformationally regulated by another prolyl isomerase - FKBP12. FKBP12 binds to the same CRMP2A sites as Pin1, but, in contrast to Pin1, it inhibits the activity of CRMP2A. Using microtubule polymerization assays and cell and neuron cultures, we show that FKBP12 inhibits CRMP2A-dependent microtubule polymerization in vitro and in vivo and reduces axon growth. Our data demonstrate that, together with phosphorylation, conformational changes catalyzed by prolyl isomerases represent a next level of positive/negative regulation of MAPs with a direct impact on microtubule dynamics and neural development.