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The Cytoskeletal Stress Response Pathway: a homeostatic system driven by Dual Leucine Zipper Kinase (DLK)

ABSTRACT: Injury to peripheral axons initiates a complex cascade of cellular responses, including cytoskeletal disassembly, axon transport disruption, and ultimately axon regeneration. Central to this process is the MAP triple kinase Dual-Leucine Zipper Kinase (DLK), activated by injury and other neuronal stressors. Here, we propose the existence of a homeostatic mechanism termed the Cytoskeletal Perturbation Response (CPR). We investigate this hypothesis by examining the response of cultured dorsal root ganglion (DRG) neurons to low dose nocodazole treatment, a cytoskeletal perturbing agent. To gain insights into DLK-dependent transcriptional changes following cytoskeletal insult, we performed bulk RNA sequencing on cultured neurons treated for 16 hours. Using a fully crossed two-factor design, we determined the interactive effect of DLK on nocodazole- dependent transcriptional changes. Our study demonstrates that cytoskeletal perturbation triggers DLK-dependent signaling cascades, leading to significant transcriptional changes. These changes involve transcription factors (Jun, Egr1, Atf3) and MAP kinase regulators (DUSPs), pointing to a regulatory network that attenuates DLK signaling. Taken together, our findings suggest that cytoskeletal perturbation activates a DLK-dependent homeostatic mechanism, the CPR, which orchestrates transcriptional changes and morphological adaptations to repair neuronal damage. The CPR bears similarities to established homeostatic responses, offering insights into the intricate processes that underlie axon regeneration and cellular repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE244883 | GEO | 2023/10/11

REPOSITORIES: GEO

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Altered gene expression in the small intestine of IE-Cpr-null mice

Project description:The NADPH-cytochrome P450 reductase (CPR) is essential for the functioning of microsomal cytochrome P450 (P450) monoxygenases. The biological functions of the CPR-dependent enzymes in the intestine are not known, despite the vast knowledge available on the biochemical properties of the various oxygenases. A mouse model with intestinal epithelium (IE)-specific Cpr-knockout (IE-Cpr-null) was recently generated in this laboratory (Zhang et al., Drug Metab. Dispos., 37, 651-657, 2009). The IE-Cpr-null mice did not display any obvious abnormalities in growth, development, or reproduction, and their intestines appeared to have a normal structure. Despite the absence of observable phenotypes, we hypothesized that loss of the enterocyte CPR expression will impact homeostasis of endogenous compounds, and expression of genes, that have critical biological function in the small intestine. In the present study, we have performed genomic analyses for enterocytes from IE-Cpr-null mice and their wild-type littermates, using Affymetrix Mouse Expression Set 430A 2.0 GeneChip Arrays. Our aim was to identify small intestinal gene-expression changes, which may shed light on potential biological roles of CPR and CPR-dependent enzymes in the small intestine. Our analysis revealed significant expression increases in P450s, transporters, cholesterol biosynthesis, and (unexpectedly) antigen presentation/processing. Further genomic and biochemical analyses revealed potential mechanisms linking CPR-dependent enzymes and the expression of major histocompatibility complex class II genes in the small intestine.

2012-04-11 | GSE35293 | GEO

Altered gene expression in the small intestine of IE-Cpr-null mice

2012-04-10 | E-GEOD-35293 | biostudies-arrayexpress

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Project description:To investigate the role of DLK in the adult brain, we generated mice in which excision of the DLK allele can be temporally controlled to avoid the lethality observed at early postnatal ages in DLK null mice (Hirai et al., 2006). This was done by crossing mice with DLK exons 2-5 flanked by loxP sites (DLKlox/lox) to a Tamoxifen inducible Cre-ERT transgene driven by the CMV early enhancer/chicken beta actin (CAG) promoter that expresses high levels of Cre-ERT in brain and most peripheral tissues (Hayashi and McMahon, 2002). DLKlox/lox /Cre-ERTpos mice (referred to as DLKlox;Crepos) displayed minimal recombination of the DLK allele in the absence of Tamoxifen and survived to adulthood. To induce DLK recombination, 10-12 week old DLKlox;Crepos mice were put on a Tamoxifen diet for three weeks combined with three high dose injections of Tamoxifen, which resulted in efficient excision of DLK in most brain regions. Although the vast majority of DLK protein was eliminated in many brain regions one week after completion of Tamoxifen dosing, a small amount of DLK protein was still present, consistent with the levels of unrecombined DLK observed by PCR in each brain region. Nonetheless, this dosing regimen achieved a reduction in DLK levels that was adequate to assess the function of this kinase in the adult CNS and thus, avoid confounding developmental phenotypes. To examine what changes in gene expression resulted from Tamoxifen induced excision of DLK, we performed microarray analysis on the hippocampi of five Tamoxifen treated DLKlox;Crepos (conditional knock-outs, cKO) and five DLKlox;Creneg (WT) aged matched controls. Gene expression of adult hippocampus was compared betwween DLK wild-type and DLK conditional knockout mice.

2013-08-28 | E-GEOD-50245 | biostudies-arrayexpress

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

2013-08-28 | GSE50245 | GEO

Altered hepatic gene expression in liver-Cpr-null and Cpr-low mice

Project description:NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895–25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPAR-gamma) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice. Keywords = Cytochrome P450 Keywords = NADPH-cytochrome P450 reductase Keywords = transgenic mice Keywords = liver Keywords = nuclear receptor Keywords: other

2005-07-16 | GSE2362 | GEO

Transcription profiling of mouse models with liver-specific deletion or global hypomorphic expression of the NADPH-cytochrome P450 reductase gene to study molecular mechanisms for the regulation of microsomal cytochrome P450 and the fatty liver phenotype.

Project description:NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895-25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPARï?¡) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice.

2007-08-31 | E-GEOD-2362 | biostudies-arrayexpress

DLK-gated responses in motoneurons following sciatic nerve crush

Project description:To profile downstream gene-expression changes regulated by DLK, we profiled motoneurons in the lumbar spinal cord using RiboTag, following sciatic nerve crush in both control and Dlk conditional knockout (Dlk ΔMN) mice. We found that DLK regulates the expression of many secreted proteins, which have the potential to influence the behavior of other cells, including the immune system.

2024-01-22 | GSE213987 | GEO

Stress-induced DLK-vesicle assembly acts as local signaling platform that drives kinase activation and neurodegeneration

Project description:Mitogen-activated protein kinases (MAPKs) drive key signaling cascades during neuronal survival and degeneration. The re-localization of kinases to specific subcellular compartments is a critical mechanism to locally control signaling activity and specificity upon stimulation. However, how MAPK signaling components tightly control their localization remains largely unknown. Here, we systematically analyzed the phosphorylation and membrane localization of all MAPKs expressed in dorsal root ganglia neurons, under control and stress conditions. We found that MAP3K12/ dual leucine zipper kinase (DLK) is the only MAPK that becomes phosphorylated and palmitoylated, and it is recruited to sphingomyelin rich vesicles upon stress. The DLK stress-induced vesicle assembly is essential for kinase activation; blocking DLK-membrane interactions inhibits downstream signaling, while DLK recruitment to ectopic subcellular structures is sufficient to induce kinase activation. We show that the localization of DLK to newly formed vesicles is essential for local signaling and inhibition of membrane internalization blocks DLK activation and protects against neurodegeneration. These data establish vesicular assemblies as dynamically regulated platforms for DLK signaling during neuronal stress responses.

| MSV000088168 | MassIVE

Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration (RNA-Seq I)

Project description:In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here we showed that knocking out myosin IIA/B in retinal ganglion cells alone either before or after optic nerve crush induced significant optic nerve regeneration. Combined Lin28a overexpression and myosin IIA/B knockout led to additive promoting effect and long-distance axon regeneration. Immunostaining, RNA sequencing and western blot analyses revealed that myosin II deletion did not affect known axon regeneration signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction bulb formation and significantly enhanced the axon extension efficiency. The study provided clear evidence that directly targeting neuronal cytoskeleton was sufficient to induce significant CNS axon regeneration, and combining altered gene expression in the soma and modified cytoskeletal dynamics in the axon was a promising approach for long-distance CNS axon regeneration

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