Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations

Plummer, Nicholas W.; Squire, Teresa L.; Srinivasan, Sudha; Huang, Elizabeth; Zawistowski, Jon S.; Matsunami, Hiroaki; Hale, Laura P.; Marchuk, Douglas A.

doi:10.1007/s00335-005-0098-8

Cited by 65 publications

(54 citation statements)

References 33 publications

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“…4,13,14,25,26 It is noteworthy, however, that the vascular defects occurred exclusively extracerebrally in Ccm2 deficient animals 13,25 and that the typical CCMlike vascular lesions were rarely observed in heterozygote Ccm1 +/−19 or Ccm2 +/− mice. 20 These findings raised the assumption that additional factors may determine whether CCMs occur in CCM gene mutation carriers. 17 Although this proposal remains speculative, one could imagine that the endothelium in CCM lesions harbors certain unique properties because the lesions have been exposed to this abnormal, yet undefined, microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Zhu

et al. 2010

FOC

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Object Loss-of-function mutations in CCM genes are frequently detected in familial cerebral cavernous malformations (CCMs). However, the current functional studies of the CCM genes in vitro have been performed mostly in commercially purchased normal cell lines and the results appeared discrepant. The fact that the cerebral vascular defects are rarely observed in CCM gene-deficient animals suggests the requirement of additional pathological background for the formation of vascular lesions. Consistent with these data, the authors assumed that silencing CCM genes in the endothelium derived from CCMs (CCM-ECs) serves as a unique and valuable model for investigating the function of the CCM genes in the pathogenesis of CCMs. To this end, the authors investigated the role and signaling of CCM2 and CCM3 in the key steps of angiogenesis using CCM-ECs. Methods Endothelial cells (ECs) derived from CCMs were isolated, purified, and cultured from the fresh operative specimens of sporadic CCMs (31 cases). The CCM2 and CCM3 genes were silenced by the specific short interfering RNAs in CCM-ECs and in control cultures (human brain microvascular ECs and human umbilical vein ECs). The efficiency of gene silencing was proven by real-time reverse transcriptase polymerase chain reaction. Cell proliferation and apoptosis, migration, tube formation, and the expression of phosphor-p38, phosphor-Akt, and phosphor-extracellular signal-regulated kinase–1 and 2 (ERK1/2) were analyzed under CCM2 and CCM3 silenced conditions in CCM-ECs. Results The CCM3 silencing significantly promoted proliferation and reduced apoptosis in all 3 types of endothelium, but accelerated cell migration exclusively in CCM-ECs. Interestingly, CCM2 siRNA influenced neither cell proliferation nor migration. Silencing of CCM3, and to a lesser extent CCM2, stimulated the growth and extension of sprouts selectively in CCM-ECs. Loss of CCM2 or CCM3 did not significantly influence the formation of the tubelike structure. However, the maintenance of tube stability was largely impaired by CCM2, but not CCM3, silencing. Western blot analysis revealed that CCM2 and CCM3 silencing commonly activated p38, Akt, and ERK1/2 in CCM-ECs. Conclusions The unique response of CCM-ECs to CCM2 or CCM3 siRNA indicates that silencing CCM genes in CCM-ECs is valuable for further studies on the pathogenesis of CCMs. Using this model system, the authors demonstrate a distinct role of CCM2 and CCM3 in modulating the different processes of angiogenesis. The stimulation of endothelial proliferation, migration, and massively growing and branching angiogenic sprouts after CCM3 silencing may potentially contribute to the formation of enriched capillary-like immature vessels in CCM lesions. The severe impairment of the tube integrity by CCM2, but not CCM3, silencing is associated with the different intracranial hemorrhage rate observed from CCM2 and CCM3 mutation carriers. The activation of p38, ERK1/2, and Akt signal proteins in CCM2- or CCM3-silenced CCM-ECs suggests a possible involvement of these common pathways in the pathogenesis of CCMs. However, the specific signaling mediating the distinct function of CCM genes in the pathogenesis of CCMs needs to be further elucidated.

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Section: Discussionmentioning

confidence: 99%

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Zhu

et al. 2010

FOC

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“…CCM2 is required for maintenance of vascular integrity in animal models (Kleaveland et al, 2009;Whitehead et al, 2009), and CCM2 mutations in humans cause cerebral cavernous malformations in the central nervous system (Akers et al, 2009;Pagenstecher et al, 2009). Although CCM disease-related phenotypes are most prominent in the vasculature, CCM2 is ubiquitously expressed in many cell and tissue types, including within the nervous system (Plummer et al, 2006).…”

Section: Ccm2 Mediates Trka Death Signaling In Pediatric Tumor Cells mentioning

confidence: 99%

On the death Trk

Harel

Costa

Fainzilber

2010

Developmental Neurobiology

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ABSTRACT:The trk family of receptor tyrosine kinases supports survival and differentiation in the nervous system. Paradoxically it has also been shown that members of the trk family can induce cell death in pediatric tumor cells of neuronal origin. Moreover, TrkA and TrkC serve as good prognostic indicators in neuroblastoma and medulloblatoma, respectively. Although the possible linkage between these observations was intriguing, until recently there was limited insight on the mechanisms involved. Recent findings suggest that TrkA might influence neuronal cell death through stimulation of p75 cleavage. An alternative p75-independent mechanism was suggested by a newly discovered interaction between TrkA and CCM2 (the protein product of the gene cerebral cavernous malformation 2). Coexpression of CCM2 with TrkA induces cell death in medulloblastoma and neuroblastoma cells, and CCM2 expression levels correlate with those of TrkA and with good prognosis in neuroblastoma patients. Thus, mechanistic clues to the enigma of trk-induced cell death have begun to emerge. Detailed elucidation of these mechanisms and their in vivo physiological significance will be of keen interest for future research. '

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“…As in Ccm1, in situ hybridization studies have shown Ccm2 mRNA expression in neurons and astrocytes as well as transient expression in meningeal and parenchymal cerebral vessels. 7,11,16 In further molecular studies, it was noted that malcavernin contains a PTB domain similar to that of ICAP1-a, suggesting an interaction between KRIT1 and malcavernin and, therefore, a common functional pathway. The similar phenotypic perturbation (failure of angiogenesis and vascular arrest during the embryonic stage) evident with Ccm1 and Ccm2 knockout mice further supports a common pathway involving the protein products of the respective genes.…”

Section: The Ccm1 Genementioning

confidence: 99%

The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications

Krisht¹,

Whitehead

Niazi³

et al. 2010

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Cerebral cavernous malformations (CCMs) are common vascular lesions of the CNS that may lead to seizures, focal neurological deficits, and fatal hemorrhagic stroke. Human genetic studies have identified 3 genes associated with CCM, and biochemical and molecular studies in mice have elucidated signaling pathways with important therapeutic implications. In this review, the authors shed light on the 3 discovered CCM genes as well as their protein products, with particular emphasis on their signal transduction pathways and their interaction with one another. Close focus is directed at mice model studies involving the Ccm2 gene product signaling pathway, revealing an important role for the use of simvastatin or other RhoA inhibitors as a therapeutic modality in the treatment of CCM. The remaining challenges to creating a more faithful CCM animal model as well as future clinical and research implications are reviewed.

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Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations

Cited by 65 publications

References 33 publications

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

On the death Trk

The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications

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