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Regulation of neural development by microtubule associated proteins and tubulin posttranslational modifications

PhD project:      Regulation of neural development by microtubule associated proteins and tubulin posttranslational modifications

 

Precise regulation of microtubule dynamics is essential for development and function of nervous system as its changes have direct impact on neuron migration, growth, branching and synapse formation. Its defects have been linked to several neurodevelopmental disorders like autism, schizophrenia or epilepsy. Among the mechanisms controlling microtubule dynamics in neurons, microtubule associated proteins (MAPs) and posttranslational modifications of tubulin seem to play the key role. We have shown that microtubule associated protein CRMP2, which regulates tubulin polymerization and axon growth, is controlled by conformational changes catalyzed by isomeraze Pin1 and that Pin1 deficiency results in altered development of nervous system. In addition, we found that changes of tubulin polyglutamylation in vivo directly induce neurodegeneration in early postnatal neurons. While both CRMP2 expression and tubulin posttranslational modifications are prominent in development, their combined regulation of neural development remains elusive.

In the project the PhD student will study the effect of tubulin posttranslational modifications on CRMP family regulation of neuron migration, axon growth and guidance in vitro and in mouse models and the effect of their deregulation on neural development. To achieve this goal, new local transgenic and knockdown mouse models of CRMP genes and tubulin modifying enzymes will be generated and analyzed using biochemical, histological and microscopy techniques.

 

Candidate’s profile (requirements):

We are seeking outstanding self-motivated candidates with master's degree or equivalent in molecular biology, biochemistry, physiology, medicine or related fields, or those expecting to obtain their degree this year. Candidates should be fluent in English. Experiences with in vivo models (mouse, rat) as well as with in vitro cell cultures and molecular biology techniques are advantage.

 

Relevant publications:

Magiera MM, et al. Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport. EMBO J. 2018 Dec 3;37(23)

Balastik M, et al., Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep. 2015 Oct 27;13(4):812-28.

 

Supervisor:        Martin Balastik, Ph.D.