Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice.
Cyclin-dependent kinase 5 (CDK5) regulates important neuronal functions via p35. p35 undergoes cleavage in response to neuronal activity and neurotoxic conditions to release its subunit p25. Although p25 has been implicated in various neurodegenerative diseases, the mechanisms by which p25 mediates neurodegenerative impairment have not been fully elucidated. We aimed to determine the role of p25-mediated neurodegeneration on neurogenesis in an inducible transgenic mouse line overexpressing p25 (p25 TG) in the forebrain. Adult neuronal progenitor cells (NPCs) were labeled with BrdU in vivo, which were significantly increased in numbers in the subventricular zone, the hippocampus, and the cortex of p25 TG mice. Consistently, more mitotic cells were observed in p25 TG mice than in controls, even in the cortex and the CA1, which are not neurogenic regions. BrdU-positive cells were negative for GFAP or γ-H2AX, suggesting that they are not astrocytes or dying cells. Neurospheres derived from the dentate gyrus and the cortex were significantly increased in p25 TG mice and can be differentiated into astrocytes and neurons. However, p25 TG decreased the long-term survival of proliferating NPCs and severely impaired adult neurogenesis. A Transwell co-culture system was used to assess the influence of p25-expressing primary neurons on adult NPCs. Co-culture with p25-expressing neurons downregulated Ki67 expression and upregulated cleaved caspase-3, indicating that the paracrine signaling in cell-cell communication is essential for NPC survival and proliferation. Moreover, increased CDK5 activity impairs Wnt activation. This study demonstrates that hyperactivation of p25 may temporarily enhance NPC proliferation, but impair their long-term survival.
Department of Neurology, The Fifth Affiliated Hospital of Guangxi Medical University & The First People's Hospital of Nanning, Nanning, Guangxi, China.|Department of Biology, Pennsylvania State University, University Park, PA, USA.
Donghua
D
Zou
Department of Biology, Pennsylvania State University, University Park, PA, USA.
Yijing
Y
Zhou
Department of Biology, Pennsylvania State University, University Park, PA, USA.|Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China.
Long
L
Liu
Department of Biology, Pennsylvania State University, University Park, PA, USA.
Fengping
F
Dong
Picower Institute for Learning and Memory-MIT, Cambridge, MA, USA.
Tianzhi
T
Shu
Picower Institute for Learning and Memory-MIT, Cambridge, MA, USA.
Ying
Y
Zhou
Picower Institute for Learning and Memory-MIT, Cambridge, MA, USA.
Li-Huei
LH
Tsai
Department of Biology, Pennsylvania State University, University Park, PA, USA.|Picower Institute for Learning and Memory-MIT, Cambridge, MA, USA.
Yingwei
Y
Mao
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001931:Brain Mapping; D049109:Cell Proliferation; D018920:Coculture Techniques; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000502:physiology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D016896:Treatment Outcome
D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse
CDK5; Gerotarget; neural progenitor; neurogenesis; p25; transgenic mice