Spindle orientation in mammalian cerebral cortical development

Abstract

In any mitotic cell, the orientation of the mitotic spindle determines the orientation of the cleavage plane and therefore the position of the two daughter cells. When combined with polarization of cellular components, spindle orientation is also a well-conserved means of generating daughter cells with asymmetric cell fates, such as progenitors and differentiated cell types. In the mammalian neocortex, the precise planar spindle orientation observed early during development is vital for symmetric proliferative divisions. During later stages, spindles can be oblique or even vertical but the role of this reorientation is somewhat less clear as asymmetric cell fates can arise independently of spindle orientation during this stage. Although decades of work have identified many key conserved regulators of spindle positioning, its precise role in cell fate determination in the mammalian neocortex has been enigmatic. Recent work focused on mInsc and LGN has now revealed an important role for spindle orientation in determination of specific asymmetric cell fates, namely intermediate progenitors and a new progenitor population, termed outer radial glia. In this way, spindle orientation helps determine the neurogenic outcome of asymmetric progenitor divisions, thereby influencing neuron output and cerebral cortical expansion.

Figure 1

Spindle orientation in mammalian epithelia. (a) Spindle orientation begins with spindle microtubule growth from the centrosome (pink). Aster microtubules polymerize and interact with the subcortical actin cytoskeleton (grey), which help position spindle poles through cortical F-actin flow [20] and myosin-10 [100], an unconventional microtubule-binding myosin [101] (inset). (b) Planar division occurs when the spindle is positioned perpendicularly to the apicobasal axis (defined by the apical domain, green). This occurs through segregation of the LGN complex (purple) from the apical domain by Par complex proteins (green) and adherens junctions (yellow). Aster microtubules are then positioned through dynein–dynactin (red) association with the LGN complex. (c) Vertical orientation (along the apicobasal axis) occurs in the presence of mInsc, which allows association of the LGN complex with the Par complex. This connection pulls the spindle pole toward the apical domain, thereby orienting the spindle vertically. In all panels, the orange line marks the basal surface.

Figure 2

Spindle orientation in the mammalian neocortex. Planar symmetric divisions (left panel) give rise to two RGs with apical (in green) and basal domains. Planar asymmetric divisions (middle panel) give rise to one RG and a neuron (N) or IP. Oblique or vertical orientation (right panel) gives rise to asymmetric cell fates, tending to generate oRGs and IPs to a greater extent [40^•,41]. In all panels, the orange line marks the basal surface.

Figure 3

Model of spindle orientation in two types of asymmetric divisions. During asymmetric planar divisions (left), LGN associates with NuMA and Gα to direct the spindle pole away from the apical domain along the planar axis. NuMA acts as the bridge between LGN at the lateral poles and dynein/dynactin, which drive spindle pole positioning through directed microtubule transport. During asymmetric oblique or vertical divisions (right), mInsc may compete for binding with LGN and displace NuMA from the LGN complex thereby uncoupling spindle pole positioning and lateral cortex anchoring relative to the apical domain.