Mitotic Spindle Asymmetry: A Wnt/PCP-Regulated Mechanism Generating Asymmetrical Division in Cortical Precursors

Abstract

The regulation of asymmetric cell division (ACD) during corticogenesis is incompletely understood. We document that spindle-size asymmetry (SSA) between the two poles occurs during corticogenesis and parallels ACD. SSA appears at metaphase and is maintained throughout division, and we show it is necessary for proper neurogenesis. Imaging of spindle behavior and division outcome reveals that neurons preferentially arise from the larger-spindle pole. Mechanistically, SSA magnitude is controlled by Wnt7a and Vangl2, both members of the Wnt/planar cell polarity (PCP)-signaling pathway, and relayed to the cell cortex by P-ERM proteins. In vivo, Vangl2 and P-ERM downregulation promotes early cell-cycle exit and prevents the proper generation of late-born neurons. Thus, SSA is a core component of ACD that is conserved in invertebrates and vertebrates and plays a key role in the tight spatiotemporal control of self-renewal and differentiation during mammalian corticogenesis.

Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis

“…However, since the spindle poles host centrosomes with different ages and composition 49 , extracellular cues could differently affect their positioning. Interestingly, Wnt signalling has been shown to promote spindle size asymmetry leading to unequal division of neural progenitors 50 . Therefore, extracellular cues could set a variety of angles in the various tissue axes through either repulsive or attractive effects.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Finally, the noncanonical PCP pathway also plays a critical role in cortical 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 development, since Wnt-7a and Vangl2 control spindle-size asymmetry during corticogenesis and are thus proposed to be key elements in the regulation of NSC self-renewal and differentiation [72,79]. This is only natural if we take into account that the PCP pathway plays a very important role in asymmetry, and that asymmetric divisions are essential for stem and progenitor cells to ultimately shape the developing brain.…”

“…Neural tube defects in KO mice [96] Neural tube defects in VANGL1/2 DKO mice [78] VANGL2 Neural tube defects in KO mice [97] Neural tube defects in VANGL1/2 DKO mice [78] Causes precocious differentiation of neural progenitors into early-born neurons [79] Regulates asymmetric division in mouse SVZ [72] ROR1/2 Implicated in neurite extension [98] Implicated in synapse formation [99] Regulates differentiation in primary mouse neural progenitors…”

Monitoring Neurogenesis in the Cerebral Cortex: an Update

“…Albeit the orientation of the mitotic spindle could fulfill a direct and instructive role in determining the cell fate of the daughter cells produced by RGPs, it has been shown that spindle-size asymmetry also coincides with asymmetric RGP division ( Figure 4B) [79]. Neurons appear to originate preferentially from the larger, and the self-renewing RGP from the smaller spindle pole.…”

“…Several models of how asymmetric RGP division can be achieved have been proposed. These models include parameters such as cleavage plane orientation, mitotic spindle-size asymmetry, dynamic distribution of polarity cues, differential inheritance of the basal process, cell cycle length and the asymmetric inheritance of the centrosome and/or ciliary membrane [79][80][81][82].…”