A CamKIIα iCre BAC allows brain‐specific gene inactivation

Casanova, Emilio; Fehsenfeld, Sandra; Mantamadiotis, Theo; Lemberger, Thomas; Greiner, Erich F.; Stewart, Andrew F.; Schütz, Günther

doi:10.1002/gene.1078

Cited by 275 publications

(318 citation statements)

References 17 publications

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“…22 The age-matched WT and c-Abl KO littermates were treated with The SH-SY5Y cell lysates used for SILAC were subjected to immunoprecipitation using an anti-phosphotyrosine antibody and immunoblotting using antibodies against p38α, phospho-p38α (T180/Y182), c-Abl, and GAPDH. The bar graph in the right panel shows the quantification of p38α tyrosine phosphorylation (ANOVA, *Po0.05, n = 3).…”

Section: Resultsmentioning

confidence: 99%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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Section: Resultsmentioning

confidence: 99%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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“…7a). These mice were crossed with aCaMKII Cre mice 35 to obtain CaMKII Cre ;syntenin flox/ þ (syntenin þ / À ) mice. Syntenin þ / À mice were born in a Mendelian ratio and could not be distinguished from their littermate controls at birth.…”

Section: Resultsmentioning

confidence: 99%

“…CSD26463). CaMKII Cre mice 35 were obtained from European Mouse Mutant Archive. Tsc2 þ /-mice were generated previously 36 Mice were maintained on a C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulindependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

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“…We chose to use CaMKII␣-Cre transgenic mice because PGC-1␣ is abundantly expressed in forebrain, including cerebral cortex, hippocampus, basal ganglia, and hypothalamus (37). Transgenic expression of Cre recombinase under the control of CaMKII␣ promoter has been widely used to inactivate genes in the forebrain (38,39). We generated PGC-1␣ flox/flox and PGC-1␣ flox/flox ; CaMKII␣-Cre (B␣KO) mice for our studies (Fig.…”

Section: Generation Of Brain-specific Pgc-1␣-deficient Mice-mentioning

confidence: 99%

Neuronal Inactivation of Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions

Lucas

et al. 2010

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1␣ have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC-1␣ in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1␣ knock-out mice (B␣KO) using calcium/calmodulin-dependent protein kinase II␣ (CaMKII␣)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1␣ null mice, B␣KO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, B␣KO mice are hypermetabolic, and similar to whole body PGC-1␣ null mice, are also resistant to dietinduced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1␣ leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1␣ null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1␣ in the control of energy balance. Our results also implicate CaMKII␣-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo.

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A CamKIIα iCre BAC allows brain‐specific gene inactivation

Cited by 275 publications

References 17 publications

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Neuronal Inactivation of Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions

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