Abstract
Neural progenitor cells (NPCs) divide and differentiate in a precisely regulated manner over time to achieve the remarkable expansion and assembly of the layered mammalian cerebral cortex. Both intrinsic signaling pathways and environmental factors control the behavior of NPCs during cortical development. Heparan sulphate proteoglycans (HSPG) are critical environmental regulators that help modulate and integrate environmental cues and downstream intracellular signals. Syndecan-1 (Sdc1), a major transmembrane HSPG, is highly enriched in the early neural germinal zone, but its function in modulating NPC behavior and cortical development has not been explored. In this study we investigate the expression pattern and function of Sdc1 in the developing mouse cerebral cortex. We found that Sdc1 is highly expressed by cortical NPCs. Knockdown of Sdc1 in vivo by in utero electroporation reduces NPC proliferation and causes their premature differentiation, corroborated in isolated cells in vitro. We found that Sdc1 knockdown leads to reduced levels of β-catenin, indicating reduced canonical Wnt signaling. Consistent with this, GSK3β inhibition helps rescue the Sdc1 knockdown phenotype, partially restoring NPC number and proliferation. Moreover, exogenous Wnt protein promotes cortical NPC proliferation, but this is prevented by Sdc1 knockdown. Thus, Sdc1 in the germinal niche is a key HSPG regulating the maintenance and proliferation of NPCs during cortical neurogenesis, in part by modulating the ability of NPCs to respond to Wnt ligands.
Highlights
Emerging from the dorsal telencephalic neuroepithelium, the mammalian cerebral cortex develops into a highly organized and complex structure
As exemplified by embryonic day 15 (E15) coronal sections (Figure 1A), the Sdc1 signal is highly enriched in both major cortical germinal zones, the ventricular zone (VZ) and the subventricular zone (SVZ) (Fig. 1B, 1C)
The Sdc1 signal is especially prominent at the apical surface of the VZ where it co-localizes with the Nestin+ endfeet of Radial glial cells (RGCs), the principal progenitor cells in the VZ (Fig. 1C)
Summary
Emerging from the dorsal telencephalic neuroepithelium, the mammalian cerebral cortex develops into a highly organized and complex structure. NPCs, which include neural stem cells (NSCs) that self-renew and restricted progenitor cells that amplify the lineage, are the founder cell population for this remarkable process [1,2] .There are two major types of NPC during cortical neurogenesis. Radial glial cells (RGCs), which are known as apical progenitor cells as they have their soma immediately next to the ventricle in the ventricular zone (VZ), are the principal progenitor cells for cortical pyramidal neurons [3,4]. RGCs initially undergo symmetric divisions that expand the progenitor population, switch to asymmetric divisions concomitant with the initiation of neurogenesis [3,5,6]. Proper construction of the cerebral cortex is achieved through precisely balanced self-renewal, proliferation and differentiation of NPCs
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