Figure 7. Model for microtubule motor recruitment during neuronal migration.

(A) Schematic depiction of the interactions between BicD2, Nesprin-2, RanBP2, and microtubule motors. The microtubule motor-binding domain (in green) within Nesprin-2, and the BicD2 Binding Domain (BBD, in green) of RanBP2 [13,32] are represented. BicD2 is shown as an elongated structure with three major coiled-coil (CC) sections implicated, respectively, in dynein, kinesin-1, or cargo binding. The LEWD-containing microtubule motor-binding region of Nesprin-2 is shown binding to BicD2 CC3 (this study). Kinesin-1 and BicD2 have been reported bind to the nucleoporin RanBP2 in a cooperative mechanism [32,54]. We speculate that Nesprin-2 might obtain a similar arrangement to explain the importance of the LEWD sequence in both myoblast [44,45] and neuronal (this study) nuclear migration. Finally, it is unclear how the less well characterized kinesin-1 binding CC2 domain of BicD2 contributes to nuclear migration in these systems. (B) Diagrammatic representation of a migrating neuron showing microtubules emanating from the centrosome, which is located ahead of the nucleus. Box (dashed line) represents the area enlarged in migrating neuron in B’. (B’) Microtubules are shown with minus ends directed upward in the direction of migration and interacting tangentially with the NE via dynein and kinesin-1. In this arrangement dynein would propel the nucleus toward the centrosome and Cortical Plate. Kinesin-1 should pull the nucleus downward, toward the microtubule plus ends, countering the dynein forces. Larger (green) and smaller (red) arrows represent the greater and lesser microtubule motor-mediated forces suggested by our data to act on the migrating cell nucleus.