Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice

Donghua Zou, Yijing Zhou, Long Liu, Fengping Dong, Tianzhi Shu, Ying Zhou, Li-Huei Tsai and Yingwei Mao _

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Oncotarget. 2016; 7:39148-39161. https://doi.org/10.18632/oncotarget.9834

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Abstract

Donghua Zou1,2,*, Yijing Zhou2,*, Long Liu2,3,*, Fengping Dong2, Tianzhi Shu4, Ying Zhou4, Li-Huei Tsai4 and Yingwei Mao2,4

1 Department of Neurology, The Fifth Affiliated Hospital of Guangxi Medical University & The First People’s Hospital of Nanning, Nanning, Guangxi, China

2 Department of Biology, Pennsylvania State University, University Park, PA, USA

3 Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China

4 Picower Institute for Learning and Memory-MIT, Cambridge, MA, USA

* These authors have contributed equally to this work

Correspondence to:

Yingwei Mao, email:

Keywords: p25; CDK5; neurogenesis; transgenic mice; neural progenitor; Gerotarget

Received: March 22, 2016 Accepted: May 29, 2016 Published: June 06, 2016

Abstract

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.


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