Cell-permeable p38 MAP kinase promotes migration of adult neural stem/progenitor cells (original) (raw)

Endogenous neural stem/progenitor cells (NPCs) can migrate toward sites of injury, but the migration activity of NPCs is insufficient to regenerate damaged brain tissue. In this study, we showed that p38 MAP kinase (p38) is expressed in doublecortin-positive adult NPCs. Experiments using the p38 inhibitor SB203580 revealed that endogenous p38 participates in NPC migration. To enhance NPC migration, we generated a cell-permeable wild-type p38 protein (PTD-p38WT) in which the HIV protein transduction domain (PTD) was fused to the N-terminus of p38. Treatment with PTD-p38WT significantly promoted the random migration of adult NPCs without affecting cell survival or differentiation; this effect depended on the cell permeability and kinase activity of the fusion protein. These findings indicate that PTD-p38WT is a novel and useful tool for unraveling the roles of p38, and that this protein provides a reasonable approach for regenerating the injured brain by enhancing NPC migration. In the embryonic brain, neural stem/progenitor cell (NPC) migration is necessary for normal brain development 1 , and a lack of NPC migration causes severe brain damage and lethality 2,3. In the adult brain, NPCs are localized to the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus, from which they migrate to the olfactory bulb through the rostral migratory stream (RMS) and the granular cell layer of the dentate gyrus of the hippocampus, respectively 4. On the other hand, in the acutely injured brain, adult NPCs from the SVZ migrate to sites of injury through blood vessels or neuronal fibers for up to 1 year after injury 5-7 ; however, the number of migrated cells is low relative to the number of residual cells in the injured site (max. 2%) 6. These observations indicate that NPC migration after injury is an endogenous regeneration response, and suggest that enhancement of this NPC migration could be useful for regeneration of damaged brain. Many factors promote NPC migration to sites of injury: stromal cell-derived factor (SDF-1) 8-11 , hepatocyte growth factor 12 , insulin-like growth factor-1 13 , stem cell factor 14 , monocyte chemotactic protein-1 14 , and vascular endothelial growth factor 15. These extracellular factors converge on several intracellular signaling factors, some of which are considered to be intracellular candidates for enhancers of NPC migration: cyclin-dependent kinase 5 (Cdk5) 3,16 , doublecortin (Dcx) 17 , c-Jun NH 2-terminal kinase (JNK) 18 , extracellular signal-regulated kinases 1 and 2 (ERK1/2) 19 , protein kinase C 20 , RhoA 21 , RhoC 22 , and Wnt/β-catenin 10. Among these factors, ERK1/2 and JNK belongs to mitogen-activated protein (MAP) kinase family, and their expression is induced after injury of brain neurons 23. p38 MAP kinase (p38, also known as stress-activated protein kinase 2 [SAPK2]), is another component of the MAP kinase family, and its expression is also elevated after injury of neurons 24 , astrocytes 24 , and microglia 25 in the brain. Chemical inhibition experiments demonstrated that sustained activation of p38 is associated with neuronal death and apoptosis 26,27. In NPCs, expression of p38 is detectable from mouse embryonic day 10 28 , and may play regulatory roles in NPC proliferation 28-31 , apoptosis 32,33 , chemokine production 34 , and cell survival 35 .