Background: Cell cycle regulation of neural progenitor cells
(NPCs) is an essential process for neurogenesis, neural development, and
repair after brain trauma. Stromal cell-derived factor-1 (SDF-1, CXCL12)
and its receptors CXCR4 and CXCR7 are well known in regulating the
migration and survival of NPCs. The effects of CXCL12 on NPCs
proliferation, cell cycle regulation, and their associated signaling pathways
remain unclear. Cyclin D1 is a protein required for progression through the
G1 phase of the cell cycle and a known downstream target of β -catenin.
Therefore, cyclin D1 plays critical roles of cell cycle regulation, proliferation,
and survival in NPCs.
Methods: Primary mouse NPCs (mNPCs) were derived from brain tissues of wild-type,
Cxcr4 knockout, or Cxcr7 knockout mice at mouse embryonic day 13.5 (E13.5). Flow
cytometry was used to perform cell cycle analysis by quantitation of DNA content. Real-time
PCR and Western blot were used to evaluate mRNA and protein expressions, respectively.
Ki67 immunostaining and TUNEL assay were used to assess the proliferation and survival of
Results: CXCL12 pretreatment led to the shortening of G0/G1 phase and lengthening of S
phase, suggesting that CXCL12 regulates cell cycle progression in mNPCs. Consistently,
CXCL12 treatment increased the expression of CyclinD1 and β -catenin, and promoted
proliferation and survival of mNPCs. Cxcr7 knockout of mNPCs blocked CXCL12-mediated
mNPCs proliferation, whereas Cxcr4 knockout mNPC did not significantly effect CXCL12-
mediated mNPCs proliferation.
Conclusion: CXCR7 plays an important role in CXCL12-mediated mNPC cell cycle
regulation and proliferation.