Nesprins and opposing microtubule motors generate a point force that drives directional nuclear motion in migrating neurons

Abstract

Nuclear migration of newly born neurons is essential for cortex formation in the brain. The nucleus is translocated by actin and microtubules, yet the actual force generated by the interplay of these cytoskeletons remains elusive. High-resolution time-lapse observation of migrating murine cerebellar granule cells revealed that the nucleus actively rotates along the direction of its translocation, independently of centrosome motion. Pharmacological and molecular perturbation indicated that spin torque is primarily generated by microtubule motors through the LINC complex in the absence of actomyosin contractility. In contrast to the prevailing view that microtubules are uniformly oriented around the nucleus, we observed that the perinuclear microtubule arrays are of mixed polarity and both cytoplasmic dynein complex and kinesin-1 are required for nuclear rotation. Kinesin-1 can exert a point force on the nuclear envelope via association with nesprins, and loss of kinesin-1 causes failure in neuronal migration in vivo Thus, microtubules steer the nucleus and drive its rotation and translocation via a dynamic, focal interaction of nesprins with kinesin-1 and dynein, and this is necessary for neuronal migration during brain development.