Abstract
Glycogen synthase kinases 3 (GSK3) α and β are expressed in the nervous system, and disruption of GSK3 signaling has been implicated in a wide range of neurodevelopmental and psychiatric disorders. Although several studies have established a role of GSK3 signaling in the nervous system, much less is known about isoform-specific functions. Here, we have examined the role of GSK3α and GSK3β in the developing neocortex by performing in utero electroporation with specific small interfering RNAs targeting each isoform. We found that depletion of either GSK3α or GSK3β commonly promoted the proliferation of neural progenitor cells in the ventricular zone, but at later stages, knocking down of each isoform resulted in distinct outcomes. In particular, the transformation of radial progenitors to intermediate progenitor cells was promoted in GSK3α-depleted cells, but markedly prevented in GSK3β-depleted cells. Moreover, knocking down of GSK3β but not GSK3α prevented the generation of upper-layer Cux1+ neurons. Consistent with the distinct outcomes, protein levels of c-Myc and β-catenin, well-known substrates of GSK3, were differentially affected by depletion of GSK3α and GSK3β. Together, these results suggest that GSK3α and GSK3β might play distinct roles in the genesis and differentiation of neuronal lineage cells during neocortex development by differential regulation of downstream signaling pathways.
Highlights
Neural progenitor cells (NPCs) are self-renewing and multipotent cells that proliferate, migrate, and differentiate in a defined temporal sequence, thereby generating layer-specific classes of excitatory neurons in the cerebral cortex (Temple, 2001; Guillemot et al, 2006; Guillemot, 2007)
We found that GSK3α and GSK3β were highly expressed in NPCs in the germinal zone and intermediate progenitor cells (IPCs) in the subventricular zone (SVZ) of the dorsal telencephalon
GSK3α and GSK3β-immunoreactive fluorescence signals were detected in the apical wall of the ventricular zone (VZ) of the dorsal telencephalon, but no immunoreactive fluorescence signals were observed when the coronal sections of the dorsal telencephalon were stained with non-immune control immunoglobulin
Summary
Neural progenitor cells (NPCs) are self-renewing and multipotent cells that proliferate, migrate, and differentiate in a defined temporal sequence, thereby generating layer-specific classes of excitatory neurons in the cerebral cortex (Temple, 2001; Guillemot et al, 2006; Guillemot, 2007). Among the progenitors are radial glial cells (RGCs), which reside in the ventricular zone (VZ). RGCs undergo stereotypical patterns of symmetrical and asymmetrical cell divisions in the developing brain and give rise to diverse types of neurons, while maintaining a pool of progenitors that can self-renew. RGCs can generate neurons indirectly via intermediate progenitor cells (IPCs), which usually undergo one symmetric terminal division in the VZ and the subventricular zone (SVZ) (Kowalczyk et al, 2009), producing two neurons that migrate to the cortical plate (CP) (Haubensak et al, 2004; Noctor et al, 2004; Englund et al, 2005; Kowalczyk et al, 2009). Abnormalities in any of such processes can result in dysfunctions of the brain and lead to neurological diseases, including a wide range of neurodevelopmental and psychiatric disorders (Raedler et al, 1998; Reif et al, 2006; Manzini and Walsh, 2011; Rossi et al, 2011; Eisch and Petrik, 2012)
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