TY - JOUR
T1 - Dual leucine zipper kinase is constitutively active in the adult mouse brain and has both stress-induced and homeostatic functions
AU - Goodwani, Sunil
AU - Fernandez, Celia
AU - Acton, Paul J.
AU - Buggia-Prevot, Virginie
AU - McReynolds, Morgan L.
AU - Ma, Jiacheng
AU - Hu, Cheng Hui
AU - Hamby, Mary E.
AU - Jiang, Yongying
AU - Le, Kang
AU - Soth, Michael J.
AU - Jones, Philip
AU - Ray, William J.
N1 - Funding Information:
Acknowledgments: We thank the Robert A and Renee E. Belfer Family Foundation and the many donors to the University of Texas MD Anderson Cancer Center who supported this work, as well as the Alzheimer’s Disease Drug Discovery Foundation (Grant 20160903, WJR).
Funding Information:
We thank the Robert A and Renee E. Belfer Family Foundation and the many donors to the University of Texas MD Anderson Cancer Center who supported this work, as well as the Alzheimer?s Disease Drug Discovery Foundation (Grant 20160903, WJR).
Publisher Copyright:
© 2020 by the authors.
PY - 2020/7/2
Y1 - 2020/7/2
N2 - Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which it transmits signals to the nucleus via retrograde transport. Here we report that in contrast to this mode of regulation, in the uninjured adult mouse cerebellum, DLK constitutively drives nuclear p-c-Jun in cerebellar granule neurons, whereas in the forebrain, DLK is similarly expressed and active, but nuclear p-c-Jun is undetectable. When neurodegeneration results from mutant human tau in the rTg4510 mouse model, p-c-Jun then accumulates in neuronal nuclei in a DLK-dependent manner, and the extent of p-c-Jun correlates with markers of synaptic loss and gliosis. This regional difference in DLK-dependent nuclear p-c-Jun accumulation could relate to differing levels of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1), whereas the forebrain contains more JIP-3 and plenty of SH3 (POSH). To characterize the functional differences between constitutive-versus injury-induced DLK signaling, RNA sequencing was performed after DLK inhibition in the cerebellum and in the non-transgenic and rTg4510 forebrain. In all contexts, DLK inhibition reduced a core set of transcripts that are associated with the JNK pathway. Non-transgenic forebrain showed almost no other transcriptional changes in response to DLK inhibition, whereas the rTg4510 forebrain and the cerebellum exhibited distinct differentially expressed gene signatures. In the cerebellum, but not the rTg4510 forebrain, pathway analysis indicated that DLK regulates insulin growth factor-1 (IGF1) signaling through the transcriptional induction of IGF1 binding protein-5 (IGFBP5), which was confirmed and found to be functionally relevant by measuring signaling through the IGF1 receptor. Together these data illuminate the complex multi-functional nature of DLK signaling in the central nervous system (CNS) and demonstrate its role in homeostasis as well as tau-mediated neurodegeneration.
AB - Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which it transmits signals to the nucleus via retrograde transport. Here we report that in contrast to this mode of regulation, in the uninjured adult mouse cerebellum, DLK constitutively drives nuclear p-c-Jun in cerebellar granule neurons, whereas in the forebrain, DLK is similarly expressed and active, but nuclear p-c-Jun is undetectable. When neurodegeneration results from mutant human tau in the rTg4510 mouse model, p-c-Jun then accumulates in neuronal nuclei in a DLK-dependent manner, and the extent of p-c-Jun correlates with markers of synaptic loss and gliosis. This regional difference in DLK-dependent nuclear p-c-Jun accumulation could relate to differing levels of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1), whereas the forebrain contains more JIP-3 and plenty of SH3 (POSH). To characterize the functional differences between constitutive-versus injury-induced DLK signaling, RNA sequencing was performed after DLK inhibition in the cerebellum and in the non-transgenic and rTg4510 forebrain. In all contexts, DLK inhibition reduced a core set of transcripts that are associated with the JNK pathway. Non-transgenic forebrain showed almost no other transcriptional changes in response to DLK inhibition, whereas the rTg4510 forebrain and the cerebellum exhibited distinct differentially expressed gene signatures. In the cerebellum, but not the rTg4510 forebrain, pathway analysis indicated that DLK regulates insulin growth factor-1 (IGF1) signaling through the transcriptional induction of IGF1 binding protein-5 (IGFBP5), which was confirmed and found to be functionally relevant by measuring signaling through the IGF1 receptor. Together these data illuminate the complex multi-functional nature of DLK signaling in the central nervous system (CNS) and demonstrate its role in homeostasis as well as tau-mediated neurodegeneration.
KW - Alzheimer’s disease
KW - Cerebellum
KW - DLK
KW - Map3k12
KW - Neurodegeneration
KW - Synaptic maintenance
KW - Tau
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UR - http://www.scopus.com/inward/citedby.url?scp=85088008572&partnerID=8YFLogxK
U2 - 10.3390/ijms21144849
DO - 10.3390/ijms21144849
M3 - Article
C2 - 32659913
AN - SCOPUS:85088008572
SN - 1661-6596
VL - 21
SP - 1
EP - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 14
M1 - 4849
ER -