Interkinetic Nuclear Migration and the Selection of Neurogenic Cell Divisions during Vertebrate Retinogenesis

Abstract

During retinal development, neuroepithelial progenitor cells divide in either a symmetric proliferative mode, in which both daughter cells remain mitotic, or in a neurogenic mode, in which at least one daughter cell exits the cell cycle and differentiates as a neuron. Although the cellular mechanisms of neurogenesis remain unknown, heterogeneity in cell behaviors has been postulated to influence this cell fate. In this study, we analyze interkinetic nuclear migration, the apical-basal movement of nuclei in phase with the cell cycle, and the relationship of this cell behavior to neurogenesis. Using time-lapse imaging in zebrafish, we show that various parameters of interkinetic nuclear migration are significantly heterogeneous among retinal neuroepithelial cells. We provide direct evidence that neurogenic progenitors have greater basal nuclei migrations during the last cell cycle preceding a terminal mitosis. In addition, we show that atypical protein kinase C (aPKC)-mediated cell polarity is essential for the relationship between nuclear position and neurogenesis. Loss of aPKC also resulted in increased proliferative cell divisions and reduced retinal neurogenesis. Our data support a novel model for neurogenesis, in which interkinetic nuclear migration differentially positions nuclei in neuroepithelial cells and therefore influences selection of progenitors for cell cycle exit based on apical-basal polarized signals.

Computational prediction of neural progenitor cell fates

“…Using these locations, we compute cell movement vectors (Δx(t), Δy(t)), , and movement directions θ(t)=tan -1 (Δy(t)/Δx(t)) . We also compute the net movement of each cell from its initial location, denoted D(t)= |(x(t),y(t))-(x(0),y(0))|, as previously reported 15 . Next, we fit an ellipse to each cell region, and compute its eccentricity e(t).…”

Detection of mitoses in embryonic epithelia using motion field analysis

“…Manual observations of many such mitoses revealed that these motions are characterised by two components: inward motion along the plane of the cell division, as at the points marked þ in Figure 2, and outward motion along an axis through the centers of the newly-formed cells, as at the points marked o and * . Interkinetic migration (Baye and Link 2007), a characteristic apical -basal motion of the nucleus associated with mitosis, appears not to be a significant driver of the observed motions, since it would produce isotropic motions. Instead, these motions, which are consistent with those predicted by 2D computer simulations (Brodland and Veldhuis 2002), are approximately normal to each other and of opposite sense.…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…Nevertheless, in the zebrafish retina, aPKC-mediated cell polarity is essential for the coordination between nuclear position and neurogenesis. Loss of aPKC resulted in increased proliferative cell divisions and reduced retinal neurogenesis (Baye and Link 2007). In that system, various parameters of interkinetic nuclear migration were found to be significantly heterogeneous among cells.…”

“…Interkinetic nuclear migration or movement is the process in which the nucleus moves within the cytoplasm of elongated neuroepithelial progenitor cells in synchronization with the cell cycle phase (Frade 2002;Baye and Link 2007). The elongated progenitors, that in the mouse span the entire cortical thickness, display a dynamic oscillation of the nucleus.…”