期刊
STEM CELLS
卷 33, 期 8, 页码 2574-2585出版社
WILEY-BLACKWELL
DOI: 10.1002/stem.2022
关键词
Chemokine receptor; Cell migration; Neural stem cell; Cell signaling
资金
- Nebraska Research Initiative [NIH S10-RR-027301]
- Eppley Cancer Center [P30CA036727]
- National Basic Research Program of China (973 Program) [2014CB965000, 2014CB965001, 2014CB96500]
- National Natural Science Foundation of China [81271419, 81271420]
- Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China [81329002]
- NIH [R01 NS 41858-01, R01 NS 061642-01]
- State of Nebraska [DHHS-LB606]
Neural progenitor cell (NPC) migration is an essential process for brain development, adult neurogenesis, and neuroregeneration after brain injury. Stromal cell-derived factor-1 (SDF-1, CXCL12) and its traditional receptor CXCR4 are well known to regulate NPC migration. However, the discovery of CXCR7, a newly identified CXCL12 receptor, adds to the dynamics of the existing CXCL12/CXCR4 pair. Antagonists for either CXCR4 or CXCR7 blocked CXCL12-mediated NPC migration in a transwell chemotaxis assay, suggesting that both receptors are required for CXCL12 action. We derived NPC cultures from Cxcr4 knockout (KO) mice and used transwell and stripe assays to determine the cell migration. NPCs derived from Cxcr4 KO mice polarized and migrated in response to CXCL12 gradient, suggesting that CXCR7 could serve as an independent migration receptor. Furthermore, Cxcr4 KO NPCs transplanted into the adult mouse striatum migrated in response to the adjacent injection of CXCL12, an effect that was blocked by a CXCR7 antagonist, suggesting that CXCR7 also mediates NPC migration in vivo. Molecular mechanism studies revealed that CXCR7 interact with Rac1 in the leading edge of the polarized NPCs in the absence of CXCR4. Both CXCR7 and Rac1 are required for extracellular signal-regulated kinases (ERK) 1/2 activation and subsequent NPC migration, indicating that CXCR7 could serve as a functional receptor in CXCL12-mediated NPC migration independent of CXCR4. Together these results reveal an essential role of CXCR7 for CXCL12-mediated NPC migration that will be important to understand neurogenesis during development and in adulthood.
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