Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

Boulday, Gwénola; Rudini, Noemi; Maddaluno, Luigi; Blécon, Anne; Arnould, Minh; Gaudric, Alain; Chapon, Françoise; Adams, Ralf H.; Dejana, Elisabetta; Tournier‐Lasserve, Elisabeth

doi:10.1084/jem.20110571

Cited by 126 publications

(161 citation statements)

References 64 publications

(106 reference statements)

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…CCM2 deletion in endothelial cells causes a defect in lumen formation of branchial arch arteries during development but does not affect apicobasal polarity in endothelial cells. 11,167 In addition, deletion of CCM3 interrupts lumen formation but not the development of branchial arch arteries. 168,169 At the biochemical level, CCM2 is required for maintaining the cytoskeleton and limiting RHOA activation.…”

Section: Ccm Proteins In Endothelial Polaritymentioning

confidence: 99%

Apicobasal polarity of brain endothelial cells

Worzfeld

Schwaninger

2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Normal brain homeostasis depends on the integrity of the blood-brain barrier that controls the access of nutrients, humoral factors, and immune cells to the CNS. The blood-brain barrier is composed mainly of brain endothelial cells. Forming the interface between two compartments, they are highly polarized. Apical/luminal and basolateral/abluminal membranes differ in their lipid and (glyco-)protein composition, allowing brain endothelial cells to secrete or transport soluble factors in a polarized manner and to maintain blood flow. Here, we summarize the basic concepts of apicobasal cell polarity in brain endothelial cells. To address potential molecular mechanisms underlying apicobasal polarity in brain endothelial cells, we draw on investigations in epithelial cells and discuss how polarity may go awry in neurological diseases.

show abstract

Section: Ccm Proteins In Endothelial Polaritymentioning

confidence: 99%

Apicobasal polarity of brain endothelial cells

Worzfeld

Schwaninger

2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…CCMs are slowflow vascular malformations with multiple lumens that are embedded in a thick collagen matrix. CCM occurs as a result of a loss-of-function mutation in any one of three genes encoding the CCM proteins, CCM1 (also known as Krev interaction trapped protein 1, KRIT1), CCM2 (also known as malcavernin, MGC4607) or CCM3 (also known as programmed cell death protein 10, PDCD10) (Labauge et al, 2007;Dejana et al, 2009a;Kleaveland et al, 2009;Whitehead et al, 2009;Boulday et al, 2011;McDonald et al, 2012). Coimmunoprecipitation experiments show that the three CCM proteins form a tripartite complex in the cytoplasm (Zawistowski et al, 2005), which might explain why the loss of any of them leads to the inactivation of the complex and causes vascular malformations that are similar in morphology.…”

Section: Mechanisms Of Induction or Inhibition Of Endothelial Permeabmentioning

confidence: 99%

“…Therefore, the CCM complex might have an important role in maintaining the correct architecture of endothelial junctions. Indeed, ablation of any CCM protein strongly affects AJs, AJ permeability and, most importantly, vascular fragility is markedly increased, resulting in lesions that frequently bleed and cause headache, seizures and eventually hemorrhagic stroke in the affected patients (Riant et al, 2010;Boulday et al, 2011). It has also been shown that upon loss of one CCM complex component, VE-cadherin and other AJ factors do not correctly localize to the basolateral side of the endothelial membrane but, instead, are diffusely localized on the cell membrane (Lampugnani et al, 2010).…”

Section: Mechanisms Of Induction or Inhibition Of Endothelial Permeabmentioning

confidence: 99%

Endothelial adherens junctions at a glance

Dejana

Orsenigo

2013

Journal of Cell Science

Self Cite

176

142

View full text Add to dashboard Cite

Adherens junctions have an important role in the control of vascular permeability. These structures are located at cell-to-cell contacts, mediate cell adhesion and transfer intracellular signals. Adhesion is mediated by cadherins, which interact homophilically in trans and form lateral interactions in cis. VE-cadherin (also known as CDH5 and CD144) is the major component of endothelial adherens junctions and is specific to endothelial cells. Endothelial cells from different types of vessels, such as lymphatic vessels, arteries and veins, show differences in junction composition and organization. Vascular permeability is increased by modifications in the expression and function of adherens junction components. In some cases these defects might be cause of pathology. In this Cell Science at a Glance article, we present the example of the so-called cerebral cavernous malformation (CCM), where adherens junctions are dismantled in the vessels contributing to brain microcirculation. This causes the loss of endothelial cell apical–basal polarity and the formation of cavernomas, which are fragile and hemorrhagic. Other diseases are accompanied by persistent alterations of vascular morphology and permeability, such as seen in tumors. It will be important to achieve a better understanding of the relationship between vascular fragility, malformations and junctional integrity in order to develop more effective therapies.

show abstract

“…Familial CCM is associated with a heterozygous germline loss-of-function mutation in KRIT1, CCM2 or PDCD10 (Cavalcanti et al, 2012). Malformation development appears to require a local second hit to remove the remaining wild-type copy of the CCM gene (Akers et al, 2009;Dammann et al, 2013;Pagenstecher et al, 2009;Stahl et al, 2008), but other factors in the neurovasculature microenvironment could potentially also have a role in lesion formation (Boulday et al, 2011;Dammann et al, 2013). Local mutations in CCM genes also cause sporadic CCM (Limaye et al, 2009), and there is a growing list of disease-causing mutations, most of which are nonsense mutations leading to a loss of function.…”

Section: Ccm Proteins Krit1mentioning

confidence: 99%

Cerebral cavernous malformation proteins at a glance

Draheim

Fisher

Boggon

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein-protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding.

show abstract

Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

Abstract: As revealed in a new model of cerebral cavernous malformations (CCM), the timing of ablation of Ccm genes determines whether or not CCM lesions arise in brain and retina venous beds.

Cited by 126 publications

References 64 publications

Apicobasal polarity of brain endothelial cells

Apicobasal polarity of brain endothelial cells

Endothelial adherens junctions at a glance

Cerebral cavernous malformation proteins at a glance

Contact Info

Product

Resources

About