Lissencephalygene(LIS1)inneuronalmigrationanddevelopment

Integration of pathways that regulate nucleokinesis during neuronal migration and a model of LIS1 mediating CLIP-170 interactions with the dynein/dynactin pathway. LIS1 can bind to MT bundles; however, phospho-LIS1 binding to MT bundles is mediated through the distal zinc finger motif of CLIP-170. When the distal zinc finger motif of CLIP-170 is mutated, the phospho-LIS1 isoform can no longer bind to MT bundles. This can also explain why p150/dynactin is not recruited to the MT bundles. CLIP-170 targets the dynein/dynactin complex to the MT, using phopho-LIS1 as an adapter, the motor complex, being in the proximity of the MT, associates with it, the initial static link to the MT provided by CLIP-170 is released by its hyperphosphorylation (step 3); and the retrograde dynein/dynactin-dependent movement of the cargo (endocytic vesicle, kinetochore, etc.) takes place. The RELN pathway is to the right, Cdk5/ p35 in the middle, and the LIS1 pathway is on the left. Doublecortin (DCX) is placed close to the LIS1 pathway based on its interaction with LIS1 and its role in microtubule dynamics.

Contributor: Kosi Gramatikoff, PhD

REFERENCES: Anthony Wynshaw-Boris and Michael J. Gambello. LIS1 and dynein motor function in neuronal migration and development Genes & Dev., Mar 2001; 15: 639 - 651. Caspi M et al. Interaction between LIS1 and doublecortin, two lissencephaly gene products Hum. Mol. Genet., Sep 2000; 9: 2205 - 2213. Frédéric M. et al. LIS1, CLIP-170's Key to the Dynein/Dynactin Pathway Mol. Cell. Biol., May 2002; 22: 3089 – 3102 Sapir T et al. LIS1 is a microtubule-associated phosphoprotein Eur. J. Biochem., Oct 1999; 265: 181 - 188. Tai CY et al. Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function J. Cell Biol., Mar 2002; 156: 959 - 968.