2019 Fiscal Year Research-status Report
Understanding how the JNK MAPK pathway regulates axon regeneration
| Project/Area Number |
19K16911
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Keywords | axon regeneration / C. elegans / JNK MAPK / TNS-1 / MXL-1 / TDPT-1 / SVH-2 / ETS-4 |
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| Outline of Annual Research Achievements |
Our previous research discovered two pathways functioning upstream of the JNK MAPK cascade in axon regeneration: the growth factor receptor SVH-2 pathway, and the integrin pathway. We discovered that TNS-1, a homolog of mammalian tensin, bridges these two pathways by interacting both with auto-phosphorylated SVH-2 via its SH2 domain, and the integrin β subunit PAT-3 via the PTB domain, thereby promoting axon regeneration.
These results were reported in the Journal of Neuroscience.
Another line of research discovered a mechanism for regulation of expression of the SVH-2 factor. Previous research indicated that SVH-2 expression, which is induced in injured neurons, depends on the transcription factors ETS-4 and CEBP-1. We found that MXL-1, a Max-like transcription factor, positively regulates axon regeneration via inhibition of TDPT-1 and preventing it from inhibiting ETS-4 via SUMOylation.
The results were reported in EMBO reports.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The current focus is on potential targets of JNK MAPK in axon regeneration. One candidate is FLN-1, an ortholog of human filamin, and known to regulate axon development and the semaphoring-plexin signaling pathway. FLN-1 was recently shown to interact with UNC-33, a CRMP1 (collapsing response mediator protein 1) ortholog, known to regulate cytoskeleton polarity and stability in neurons. Both fln-1 and unc-33 mutants displayed defects in axon regeneration, and we currently investigate their relationship and possible regulation by the JNK pathway in axon regeneration.
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| Strategy for Future Research Activity |
One line of research will attempt to characterize the functional relationship between FLN-1, UNC-33 and the JNK MAPK pathway in axon regeneration, as well as the role of these factors in controlling cytoskeletal dynamics during the regeneration process.
Another one will focus on potential transcriptional targets of the JNK pathway that are induced via the transcription factor FOS-1, such as the EF-hand domain family member EFHD-1, the annexin A13 homologue NEX-1, and the actin monomer-binding TTH-1.
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| Causes of Carryover |
The amount requested will be used for purchasing consumable goods and services necessary for DNA work, generation of mutants, microscopy etc. experiments as stated in the research plan.
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