Involvement of p38 in Age-Related Decline in Adult Neurogenesis via Modulation of Wnt Signaling

Yoshitaka Kase, Kinya Otsu, Takuya Shimazaki, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


Neurogenesis in specific brain regions in adult mammals decreases with age. Progressive reduction in the proliferation of neural stem and progenitor cells (NS/PCs) is a primary cause of this age-associated decline. However, the mechanism responsible for this reduction is poorly understood. We identify p38 MAPK as a key factor in the proliferation of neural progenitor cells (NPCs) in adult neurogenic niches. p38 expression in adult NS/PCs is downregulated during aging. Deletion of p38α in NS/PCs specifically reduces the proliferation of NPCs but not stem cells. Conversely, forced expression of p38α in NS/PCs in the aged mouse subventricular zone (SVZ) restores NPC proliferation and neurogenesis, and prevents age-dependent SVZ atrophy. We also found that p38 is necessary for suppressing the expression of Wnt antagonists DKK1 and SFRP3, which inhibit the proliferation of NPCs. Age-related reduction in p38 thus leads to decreased adult neurogenesis via downregulation of Wnt signaling. Kase et al. show that p38 expression in neural stem and progenitor cells (NS/PCs) in the adult brain decreases with aging. This reduction specifically causes proliferation defect in neural progenitor cells (NPCs), leading to the age-dependent decline of adult neurogenesis. Conversely, overexpression of p38α in NS/PCs in the aged brain restores NPC proliferation without exhaustion of neural stem cells.

Original languageEnglish
Pages (from-to)1313-1328
Number of pages16
JournalStem cell reports
Issue number6
Publication statusPublished - 2019 Jun 11


  • DKK1
  • SFRP3
  • Wnt signaling
  • adult neurogenesis
  • aging
  • neural progenitor cell
  • neural stem cell
  • p38
  • transit-amplifying cell

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


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