Dynamic Interaction Between Microtubules and the Nucleus Regulates Nuclear Movement During Neuronal Migration

Abstract

Fine structures of the mammalian brain are formed by neuronal migration during development. Newborn neurons migrate long distances from the germinal zone to individual sites of function by squeezing their largest cargo, the nucleus, through the crowded neural tissue. Nuclear translocation is thought to be orchestrated by microtubules, actin, and their associated motor proteins, dynein and myosin. However, where and how the cytoskeletal forces are converted to actual nuclear movement remains unclear. Using high-resolution confocal imaging of live migrating neurons, we demonstrated that microtubule-dependent forces are directly applied to the nucleus via the linker of nucleoskeleton and cytoskeleton complex, and that they induce dynamic nuclear movement, including translocation, rotation, and local peaking. Microtubules bind to small points on the nuclear envelope via the minus- and plus-oriented motor proteins, dynein and kinesin-1, and generate a point force independent of the actin-dependent force. Dynamic binding of microtubule motors might cause a continuously changing net force vector acting on the nucleus and results in a stochastic and inconsistent movement of the nucleus, which are seen in crowded neural tissues.

Cytoskeletal control of nuclear migration in neurons and non-neuronal cells

“…It is possible that dynamic, short, bi-directional movements by opposing motors might adjust the precise nuclear position and help it pass through the narrow interstitial pores, a process that generates high mechanical stress. 51 )…”

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

“…One significant role of Kinesin-1 during EMP appears to be deforming the nuclei, which engages a sub-network of effectors of core EMP components (Figure 9C). A role of Kinesin-1 in nuclear morphogenesis has been found in numerous organisms (Bone et al, 2016; Fridolfsson et al, 2010; Fridolfsson and Starr, 2010; Lottersberger et al, 2015; Roux et al, 2009; Simon and Wilson, 2011; Splinter et al, 2010; Tanenbaum et al, 2011; Wilson and Holzbaur, 2015; Wu and Kengaku, 2018; Wu et al, 2018). Moreover, in Drosophila Kinesin-1 acts together with JIP proteins to position nuclei (Schulman et al, 2014).…”

“…But the cytoskeleton can also itself act to deform the nucleus, and in turn regulate cell behaviour and fate; perhaps the best example of which is the separation of chromatin during cell division by the mitotic spindle 44 . The cytoskeleton has a role in shaping the nucleus as migrating cells pass through confined spaces during development and disease 10,[45][46][47][48] . Finally, the cytoskeleton deforms to nucleus to promote differentiation 49, 50 , and DNA repair 51 .…”

“…Thus MTs which bridge cell-cell adhesions and the nucleus can act to promote nuclear mechanical stability and decrease the effective deformability of the nucleus 6,11,43 .But the cytoskeleton can also itself act to deform the nucleus, and in turn regulate cell behaviour and fate; perhaps the best example of which is the separation of chromatin during cell division by the mitotic spindle 44 . The cytoskeleton has a role in shaping the nucleus as migrating cells pass through confined spaces during development and disease 10,[45][46][47][48] . Finally, the cytoskeleton deforms to nucleus to promote differentiation 49, 50 , and DNA repair 51 .In addition to the cytoskeleton, another key factor in determining nuclear deformability is the composition of the nuclear lamina -which is comprised primarily of LMNA and LMNB proteins.The LMNA:LMBA ratio determines the viscoelasticity of the nucleus.…”

Randomness in microtubule dynamics: an error that requires correction or an inherent plasticity required for normal cellular function?

“…MT motor dynamic binding causes a constantly altering net force vector. This trajectory turns on the nucleus and leads to a stochastic and varying nuclear movement that is viewed in congested neural tissues (Wu and Kengaku, ). Dynamic nuclei are associated with several fundamental biological processes, among them cell migration, cell division, and fertilization.…”