Ndel1 Operates in a Common Pathway with LIS1 and Cytoplasmic Dynein to Regulate Cortical Neuronal Positioning

Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG and Tsai LH
Source: Neuron
Publication Date: (2004)
Issue: 44(2): 263-277
Research Area:
Cells used in publication:
Neuron, cortical, mouse
Species: mouse
Tissue Origin: brain
Nucleofectorâ„¢ I/II/2b
Primary mouse cortical neurons were transfected with control, Ndel1, LIS1, or DHC (dynein heavy chain) RNAi constructs. To detect the centrosome, cortical neurons were cotransfected with RFP-Centrin II, EGFP, and control Ndel1, LIS1, or DHC RNAi constructs.
Correct neuronal migration and positioning during cortical development are essential for proper brain function. Mutations of the LIS1 gene result in human lissencephaly (smooth brain), which features misplaced cortical neurons and disarrayed cerebral lamination. However, the mechanism by which LIS1 regulates neuronal migration remains unknown. Using RNA interference (RNAi), we found that the binding partner of LIS1, NudE-like protein (Ndel1, formerly known as NUDEL), positively regulates dynein activity by facilitating the interaction between LIS1 and dynein. Loss of function of Ndel1, LIS1, or dynein in developing neocortex impairs neuronal positioning and causes the uncoupling of the centrosome and nucleus. Overexpression of LIS1 partially rescues the positioning defect caused by Ndel1 RNAi but not dynein RNAi, whereas overexpression of Ndel1 does not rescue the phenotype induced by LIS1 RNAi. These results provide strong evidence that Ndel1 interacts with LIS1 to sustain the function of dynein, which in turn impacts microtubule organization, nuclear translocation, and neuronal positioning.