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...
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| Format: | Article |
| Language: | en_US |
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Impact Journals, LLC
2016
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| Online Access: | http://hdl.handle.net/1721.1/103584 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1811073773942603776 |
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| author | Zou, Donghua Zhou, Yijing Liu, Long Dong, Fengping Shu, Tianzhi Zhou, Ying Tsai, Li-Huei Mao, Yingwei |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Zou, Donghua Zhou, Yijing Liu, Long Dong, Fengping Shu, Tianzhi Zhou, Ying Tsai, Li-Huei Mao, Yingwei |
| author_sort | Zou, Donghua |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:38:23Z |
| format | Article |
| id | mit-1721.1/103584 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:38:23Z |
| publishDate | 2016 |
| publisher | Impact Journals, LLC |
| record_format | dspace |
| spelling | mit-1721.1/1035842022-09-26T12:49:00Z Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice Zou, Donghua Zhou, Yijing Liu, Long Dong, Fengping Shu, Tianzhi Zhou, Ying Tsai, Li-Huei Mao, Yingwei Picower Institute for Learning and Memory Shu, Tianzhi Zhou, Ying Tsai, Li-Huei Mao, Yingwei 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. Brain & Behavior Research Foundation (NARSAD Young Investigator Award) American Heart Association (American Heart Scientist Development Award) National Institutes of Health (U.S.) (NIH R01AG046174) National Natural Science Foundation (China) (Grant No. 81560205) National University of Defense Technology (China) (Research Foundation (JC 14-02-01)) Neurodegeneration Consortium Glenn Foundation for Medical Research 2016-07-13T15:08:40Z 2016-07-13T15:08:40Z 2016-06 2016-03 Article http://purl.org/eprint/type/JournalArticle 1949-2553 http://hdl.handle.net/1721.1/103584 Zou, Donghua, Yijing Zhou, Long Liu, Fengping Dong, Tianzhi Shu, Ying Zhou, Li-Huei Tsai, and Yingwei Mao. "Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice." Oncotarget 7:26 (June 2016), p. 39148-39161. https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.18632/oncotarget.9834 Oncotarget Creative Commons Attribution http://creativecommons.org/licenses/by/3.0/ application/pdf Impact Journals, LLC Impact Journals |
| spellingShingle | Zou, Donghua Zhou, Yijing Liu, Long Dong, Fengping Shu, Tianzhi Zhou, Ying Tsai, Li-Huei Mao, Yingwei Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title | Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title_full | Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title_fullStr | Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title_full_unstemmed | Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title_short | Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice |
| title_sort | transient enhancement of proliferation of neural progenitors and impairment of their long term survival in p25 transgenic mice |
| url | http://hdl.handle.net/1721.1/103584 https://orcid.org/0000-0003-1262-0592 |
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