TACE/ADAM17 Is Essential for Oligodendrocyte Development and CNS Myelination

Palazuelos, Javier; Crawford, Howard C.; Klingener, Michael; Sun, Bingru; Karelis, Jason; Raines, Elaine W.; Aguirre, Adán

doi:10.1523/jneurosci.1220-14.2014

Cited by 42 publications

(35 citation statements)

References 44 publications

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“…Surprisingly, our in vivo analyses indicate that ADAM17 expressed in OL is not required for developmental CNS myelination. These results are in contrast with a study showing that ADAM17 expressed in OPCs is required for CNS myelination (Palazuelos et al, ). In this former study, the authors used an inducible PDGFRα‐Cre ERT2 transgenic line (Rivers et al, ) to ablate Adam17 expression in postnatal OPCs, whereas we used a different Cre line (Lappe‐Siefke et al, ) that has been previously extensively used to obtain efficient recombination in OL (Benninger et al, ; Bremer et al, ; Funfschilling et al, ; Saher et al, ).…”

Section: Discussioncontrasting

confidence: 99%

“…Moreover, since ADAM17 is expressed in different cell types in the CNS (Karkkainen et al, ), it is possible that expression in cells other than OL might dilute the effective recombination we observed. Nevertheless, it is also possible that glial ADAM17 might have different roles during development and in CNS myelination, being important for proper timing of OPC cell cycle exit (Palazuelos et al, ) and being dispensable in later stages of OL development and maturation (Watkins et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…In the CNS, ADAM17 is expressed throughout the parenchyma (Karkkainen, Rybnikova, Pelto‐Huikko, & Huovila, ). Further, previous studies have reported that ADAM17 expressed in OPCs is important for CNS myelination in development and in remyelination (Palazuelos et al, ; Palazuelos, Klingener, Raines, Crawford, & Aguirre, ).…”

Section: Introductionmentioning

confidence: 95%

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Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Fredrickx

Colombo

Canevazzi

et al. 2019

Glia

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Myelin, one of the most important adaptations of vertebrates, is essential to ensure efficient propagation of the electric impulse in the nervous system and to maintain neuronal integrity. In the central nervous system (CNS), the development of oligodendrocytes and the process of myelination are regulated by the coordinated action of several positive and negative cell‐extrinsic factors. We and others previously showed that secretases regulate the activity of proteins essential for myelination. We now report that the neuronal α‐secretase ADAM17 controls oligodendrocyte differentiation and myelin formation in the CNS. Ablation of Adam17 in neurons impairs in vivo and in vitro oligodendrocyte differentiation, delays myelin formation throughout development and results in hypomyelination. Furthermore, we show that this developmental defect is, in part, the result of altered Notch/Jagged 1 signaling. Surprisingly, in vivo conditional loss of Adam17 in immature oligodendrocytes has no effect on myelin formation. Collectively, our data indicate that the neuronal α‐secretase ADAM17 is required for proper CNS myelination. Further, our studies confirm that secretases are important post‐translational regulators of myelination although the mechanisms controlling CNS and peripheral nervous system (PNS) myelination are distinct.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Fredrickx

Colombo

Canevazzi

et al. 2019

Glia

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“…5 Moreover, in recent years cell-specific expression of AT 1a R, in the CNS, has been shown to contribute to neurogenic hypertension 10,27,28 and other ailments. 29 Since AT 1a R and ADAM17 co-exist on various cell types, including endothelial cells, 30 vascular smooth muscle cells, 31 glial cells and neurons, 32 the contribution of cell-specific ADAM17 activation to the development of hypertension must be determined to insure selective targeting. To address the contribution of neuronal AT 1a R to ADAM17 activation, we generated a cell-specific knockout mouse by taking advantage of the neuron-specific Nefh promoter.…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Sriramula

Xia

et al. 2017

Circulation Research

159

166

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Rationale Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated. Objective To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process. Methods and Results Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting Ang II into Ang-(1–7) in human cerebrospinal fluid (CSF). We also observed an increase in ACE2 activity in the CSF of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor (TNF)-α in those CSF samples confirmed that ADAM17 was up-regulated in the hypertensive patients’ brain. To further assess the interaction between brain renin-angiotensin system and ADAM17, we generated mice lacking Angiotensin II type 1 receptors (AT1R) specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 up-regulation during DOCA-salt hypertension occurs selectively on neurons and neuronal AT1R are indispensable to this process. Mechanistically, reactive oxygen species (ROS) and extracellular signal-regulated kinase (ERK) were found to mediate ADAM17 activation. Conclusions Our data demonstrate that AT1R promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.

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“…However, the targeted deletion of ADAM17 in oligodendrocytes leads to defects in myelination and in exploratory behavior in mice (33), and inactivation of the EGFR results in progressive neurodegeneration (34). Because iR1 −/− mice are indistinguishable from their wild-type littermates during routine handling and do not display evident histopathological brain defects, future studies will be necessary to learn more about the function of ADAM17 and iRhom1 in the brain and whether iR1 −/− mice could have subtle defects in the brain or cognitive or behavioral abnormalities that were not evident in the analysis performed here.…”

Section: F) (G and H)mentioning

confidence: 99%

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Li¹,

Maretzky²,

Weskamp³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

208

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The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17 −/− mice die perinatally with open eyes, like Egfr −/− mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2 −/− mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2 −/− double knockout mice resemble Adam17 −/− and Egfr −/− mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2 −/− tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFRdependent pathologies.inactive Rhomboid proteins | a disintegrin and metalloprotease 17 | epidermal growth factor receptor | heparin-binding epidermal growth factor | transforming growth factor alpha

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TACE/ADAM17 Is Essential for Oligodendrocyte Development and CNS Myelination

Cited by 42 publications

References 44 publications

Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

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TACE/ADAM17 Is Essential for Oligodendrocyte Development and CNS Myelination

Cited by 42 publications

References 44 publications

Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination

Clinical Relevance and Role of Neuronal AT 1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

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Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension