REDUCTION OF MICROTUBULE CATASTROPHE EVENTS BY LIS1, PLATELET-ACTIVATING-FACTOR ACETYLHYDROLASE SUBUNIT

Forming the structure of the human brain involves extensive neuronal m igration, a process dependent on cytoskeletal rearrangement, Neuronal migration is believed to be disrupted in patients exhibiting the devel opmental brain malformation lissencephaly, Previous studies have shown that LIS1, the defective gene found in patients with lissencephaly, i s a subunit of the platelet-activating factor acetylhydrolase. Our res ults indicated that LIS1 has an additional function, By interacting wi th tubulin it suppresses microtubule dynamics, We detected LIS1 intera ction with microtubules by immunostaining and co-assembly, LIS1-tubuli n interactions were assayed by co-immunoprecipitation and by surface p lasmon resonance changes, Microtubule dynamic measurements in vitro in dicated that physiological concentrations of LIS1 indeed reduced micro tubule catastrophe events, thereby resulting in a net increase in the maximum length of the microtubules. Furthermore, the LIS1 protein conc entration in the brain, measured by quantitative Western blots, is hig h and is approximately one-fifth of the concentration of brain tubulin , Our new findings show that LIS1 is a protein exhibiting several cell ular interactions, and the interaction with the cytoskeleton may prove to be the mode of transducing a signal generated by platelet-activati ng factor, We postulate that the LIS1-cytoskeletal interaction is impo rtant for neuronal migration, a process that is defective in lissencep haly patients.