scholarly journals DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity

2011 ◽  
Vol 194 (5) ◽  
pp. 751-764 ◽  
Author(s):  
Arundhati Sengupta Ghosh ◽  
Bei Wang ◽  
Christine D. Pozniak ◽  
Mark Chen ◽  
Ryan J. Watts ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Scaffolding Protein ◽  
Axon Degeneration ◽  
Jnk Signaling ◽  
Signaling Complex ◽  
Neuronal Populations ◽  
Neuronal Homeostasis ◽  
Stress Response Pathway

The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.

scholarly journals Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration

2013 ◽  
Vol 210 (12) ◽  
pp. 2553-2567 ◽  
Author(s):  
Christine D. Pozniak ◽  
Arundhati Sengupta Ghosh ◽  
Alvin Gogineni ◽  
Jesse E. Hanson ◽  
Seung-Hye Lee ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Receptor Activation ◽  
Scaffolding Protein ◽  
Glutamate Signaling ◽  
Postsynaptic Density Proteins ◽  
Primary Driver

Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid–induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.

scholarly journals Palmitoylation Couples DLK to JNK3 to Facilitate Pro-degenerative Axon-to-Soma Signaling

2020 ◽  
Author(s):  
Jingwen Niu ◽  
Sabrina M. Holland ◽  
Andrea Ketschek ◽  
Kaitlin M. Collura ◽  
Takashi Hayashi ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Positive Feedback ◽  
Leucine Zipper ◽  
Retrograde Signaling ◽  
Neuronal Responses ◽  
Mitogen Activated Protein Kinases ◽  
Jnk Signaling ◽  
Highly Active ◽  
Mitogen Activated Protein

SummaryDual Leucine-zipper Kinase (DLK, a MAP3K) mediates neuronal responses to diverse injuries and insults via c-Jun N-terminal Kinase (JNK) family Mitogen-activated Protein Kinases (MAPKs). It is unclear why DLK couples to JNKs in mammalian neurons versus other MAPKs, especially because some invertebrate DLK orthologs couple instead to the related p38 family MAPKs. Here we identify two mechanisms that potentially explain this DLK-JNK coupling. First, neural-specific JNK3, but not p38-MAPK, catalyzes positive feedback phosphorylation of DLK that further activates DLK and locks the DLK-JNK3 module in a highly active state. Furthermore, the pro-degenerative JNK2 and JNK3, but not the related JNK1, are endogenously palmitoylated. Moreover, palmitoylation targets both DLK and JNK3 to the same axonal vesicles and JNK3 palmitoylation is essential for pro-degenerative axonal retrograde signaling in vivo. These findings provide insights into DLK-JNK signaling relevant to multiple neuropathological conditions and answer long-standing questions regarding the selective pro-degenerative roles of JNK2/3.

scholarly journals Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Martin Larhammar ◽  
Sarah Huntwork-Rodriguez ◽  
Zhiyu Jiang ◽  
Hilda Solanoy ◽  
Arundhati Sengupta Ghosh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Stress Signaling ◽  
Jnk Signaling ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Neuronal Stress

The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4). Disruption of PERK signaling delays neurodegeneration without reducing JNK signaling. Furthermore, DLK is both sufficient for PERK activation and necessary for engaging the ISR subsequent to JNK-mediated retrograde injury signaling. These findings identify DLK as a central regulator of not only JNK but also PERK stress signaling in neurons, with both pathways contributing to neurodegeneration.

Chemotherapy-induced neuronal dysfunction in the absence of axon degeneration.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15091-e15091
Author(s):  
Stephen Nick Housley ◽  
Ann Marie Flores ◽  
Allison B. Wang ◽  
Eric J. Perreault ◽  
Paul Nardelli ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Neuronal Degeneration ◽  
Transcriptional Profiling ◽  
Immunohistochemical Analysis ◽  
Conclusive Evidence ◽  
Nerve Degeneration ◽  
Axon Degeneration ◽  
Molecular Evidence ◽  
Platinum Based Chemotherapy

e15091 Background: Colorectal cancer is one of the three most prevalent cancers. Mortality rates have largely decreased due, in part, to advanced treatments such as platinum-based chemotherapy (e.g. oxaliplatin – OX). Unfortunately, OX induces severe off-target, neurotoxic side-effects in the sensory nervous system that can limit or end treatment and diminish patient quality of life for years. Patient symptoms are often attributed to dying-back degeneration of primary sensory axons despite the absence of conclusive evidence. We tested the hypothesis that proprioceptive disorders persisting after chemotherapy result solely from axon degeneration of muscle proprioceptors. Methods: We used a rat model to test our hypothesis. In a rodent model of OX clinical cancer treatment, one that exhibits sensorimotor deficits in a test of proprioceptive behavior, we performed single-neuron in vivo electrophysiological and immunohistological experiments. We then profiled transcriptomes of sensory neurons to gain unbiased insight into molecular evidence of degeneration. We compared the OX group of rats (n = 18) to healthy, control rats (n = 6) using hierarchical Bayesian analysis. Results: We found no evidence for sensory axon degeneration in electrophysiologic measures of axon conduction or in immunohistochemical analysis of the axon terminals of sensory neurons, OX and control rats were indistinguishable by these measures. Unbiased transcriptional profiling gave little evidence of neuronal degeneration, although genes related to axon transport showed signs of dysregulation. Structural degeneration was also ruled out by finding that all sensory neurons fired in response to stretch. Nonetheless, anomalous firing patterns were observed, e.g. decreased spike activity in response to mechanosensory stimulation, consistent with changes in ion channel physiology. Conclusions: Our findings reject the hypothesis that nerve degeneration is required to explain OX-related sensorimotor disorders. Our research suggests biological mechanisms that are alternative to axon degeneration in explaining sensorimotor changes due to OX.

scholarly journals Regulation of a bacterial histidine kinase by a phase separating scaffolding protein

2021 ◽  
Author(s):  
Chao Zhang ◽  
Wei Zhao ◽  
Samuel W Duvall ◽  
Kimberly Kowallis ◽  
William Seth Childers
Keyword(s):  
Cell Fate ◽  
Histidine Kinase ◽  
Asymmetric Cell Division ◽  
Caulobacter Crescentus ◽  
Scaffolding Protein ◽  
Signaling Complex ◽  
Intrinsically Disordered ◽  
Condensate Formation

Scaffolding proteins customize the response of signaling networks to support cell development and behaviors. We investigated how the bacterial scaffolding protein PodJ regulates the histidine kinase PleC involved in the asymmetric cell division of Caulobacter crescentus. We reconstituted the PleC-PodJ signaling complex through both heterologous expression in E. coli and in vitro studies. In vitro PodJ phase separates as a biomolecular condensate that recruits and inhibits PleC kinase activity. By constructing an in vivo PleC-CcaS chimeric histidine kinase reporter assay, we have demonstrated how PodJ leverages its intrinsically disordered region (IDR) to bind and regulate PleC-CcaS signaling. Moreover, we observed that full-length PodJL regulates PleC-CcaS signaling, while a truncated PodJs could not regulate signaling activity. These results support a model where PodJ biomolecular condensate formation regulates the localization and activity of the cell fate determining kinase PleC.

scholarly journals C. elegans germ granules require both assembly and localized regulators for mRNA repression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Scott Takeo Aoki ◽  
Tina R. Lynch ◽  
Sarah L. Crittenden ◽  
Craig A. Bingman ◽  
Marvin Wickens ◽  
...  
Keyword(s):  
Liquid Droplet ◽  
Scaffolding Protein ◽  
P Granules ◽  
C Elegans ◽  
Cytoplasmic Rna ◽  
And Function ◽  
Rnp Granules ◽  
Key Residues ◽  
Reporter Mrna

AbstractCytoplasmic RNA–protein (RNP) granules have diverse biophysical properties, from liquid to solid, and play enigmatic roles in RNA metabolism. Nematode P granules are paradigmatic liquid droplet granules and central to germ cell development. Here we analyze a key P granule scaffolding protein, PGL-1, to investigate the functional relationship between P granule assembly and function. Using a protein–RNA tethering assay, we find that reporter mRNA expression is repressed when recruited to PGL-1. We determine the crystal structure of the PGL-1 N-terminal region to 1.5 Å, discover its dimerization, and identify key residues at the dimer interface. Mutations of those interface residues prevent P granule assembly in vivo, de-repress PGL-1 tethered mRNA, and reduce fertility. Therefore, PGL-1 dimerization lies at the heart of both P granule assembly and function. Finally, we identify the P granule-associated Argonaute WAGO-1 as crucial for repression of PGL-1 tethered mRNA. We conclude that P granule function requires both assembly and localized regulators.

scholarly journals Overexpressing the HD-Zip class II transcription factor EcHB1 from Eucalyptus camaldulensis increased the leaf photosynthesis and drought tolerance of Eucalyptus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Keisuke Sasaki ◽  
Yuuki Ida ◽  
Sakihito Kitajima ◽  
Tetsu Kawazu ◽  
Takashi Hibino ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Leaf Area ◽  
Leucine Zipper ◽  
Eucalyptus Grandis ◽  
Eucalyptus Camaldulensis ◽  
Class Ii ◽  
Cell Multiplication ◽  
Leaf Photosynthesis ◽  
Unit Leaf

Abstract Alteration in the leaf mesophyll anatomy by genetic modification is potentially a promising tool for improving the physiological functions of trees by improving leaf photosynthesis. Homeodomain leucine zipper (HD-Zip) transcription factors are candidates for anatomical alterations of leaves through modification of cell multiplication, differentiation, and expansion. Full-length cDNA encoding a Eucalyptus camaldulensis HD-Zip class II transcription factor (EcHB1) was over-expressed in vivo in the hybrid Eucalyptus GUT5 generated from Eucalyptus grandis and Eucalyptus urophylla. Overexpression of EcHB1 induced significant modification in the mesophyll anatomy of Eucalyptus with enhancements in the number of cells and chloroplasts on a leaf-area basis. The leaf-area-based photosynthesis of Eucalyptus was improved in the EcHB1-overexpression lines, which was due to both enhanced CO2 diffusion into chloroplasts and increased photosynthetic biochemical functions through increased number of chloroplasts per unit leaf area. Additionally, overexpression of EcHB1 suppressed defoliation and thus improved the growth of Eucalyptus trees under drought stress, which was a result of reduced water loss from trees due to the reduction in leaf area with no changes in stomatal morphology. These results gave us new insights into the role of the HD-Zip II gene.

Sign in / Sign up

Export Citation Format

Share Document