Spindle Orientation-Independent Control of Cell Fate Determination by RGS3 and KIF20A

It was proposed that similar to its role in the invertebrate nervous system, mitotic spindle orientation (or cell cleavage plane orientation) of a dividing neural progenitor cell specifies the fate of daughter cells in the mammalian brain, modulating the production of neurons via symmetric versus asymmetric cell divisions during the course of neurogenesis. Experimental tests of the sufficiency of spindle/cleavage plane orientation in mammalian cell fate determination have yielded conflicting results. On the other hand, the necessity of spindle/cleavage plane orientation in mammalian cell fate determination has not yet been addressed. Here we examined the necessity of spindle/cleavage plane orientation during cortical neurogenesis in mice with loss-of-function of the RGS3-KIF20A interaction axis. We present evidence that while inactivation of RGS3 or KIF20A was linked to a shift in neural progenitor cells from proliferative to differentiative divisions in the developing cortex, these genetic mutations did not lead to anticipated alteration in the orientation of spindle/cleavage plane. Our results indicate that the RGS3-KIF20A axis regulates the balance between proliferation and differentiation in the mammalian cortex employing a mechanism independent of spindle/cleavage plane orientation. These data also caution against using spindle/cleavage plane orientation as the synonym for cell fate determination.